Emile Chen - Academia.edu (original) (raw)

Papers by Emile Chen

Research paper thumbnail of Model-Based Virtual PK/PD Exploration and Machine Learning Approach to Define PK Drivers in Early Drug Discovery

Journal of medicinal chemistry, Feb 20, 2024

Research paper thumbnail of A model for spatiotemporal frequency responses in the X cell pathway of the cat's retina

Vision Research, 1989

A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus... more A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus at the cornea, to cones, to X-type ganglion cells. The model contains elements representing the eye's optics, phototransduction, gain control, spatiotemporal processing by cell layers, and pure delay. Centresurround antagonism in the model arises through the presence of a centre element producing a small spatial spread of signals, and an antagonistic element producing a larger spread. Two arrangements were tried, feedforward and feedback, in which the antagonistic element's output was subtracted from the centre element's outptB, and input, respectively. The model was fitted to empirical spatial and temporal frequency responses collected by Frishman et al. (1987), and accounted qualitatively for these data in the feedback, but not the feedforward, arrangement. The model's centre pathway comprises a cascade of low-pass spatial filters, as does the surround pathway. As a consequence, the spatial frequency responses for these two pathways closely approximate Gaussian functions of spatial frequency, and the spatial frequency response of the complete model at low temporal frequency closely matches that of the difference of Gaussians model. Cat Retina Ganglion cell Spatial frequency Temporal frequency

Research paper thumbnail of Applications of Model-Based Target Pharmacology Assessment in Defining Drug Design and DMPK Strategies: GSK Experiences

Journal of Medicinal Chemistry, May 2, 2022

Research paper thumbnail of Gastric pH and Gastric Residence Time in Fasted and Fed Conscious Cynomolgus Monkeys Using the Bravo® pH System

Pharmaceutical Research, Jul 6, 2007

To measure fasted and fed gastric pH and gastric residence time (GRT) in Cynomolgus monkeys using... more To measure fasted and fed gastric pH and gastric residence time (GRT) in Cynomolgus monkeys using Bravo radiotelemetry capsules. Continuous pH measurements were recorded with Bravo capsules, which were either attached to the monkeys' stomach or administered as free capsules. Meals (either slurry or standard), were administered at designated times with monkeys chair-restrained during slurry meal ingestion. From the attached capsule studies, the fasted gastric pH (~1.9-2.2) was consistent among monkeys. Under fasted conditions, pH spikes were infrequently observed (once every 7.9 min to 3.6 h) with peaks reaching pH 9.4 and having short durations (<1 min). After feeding, the gastric pH rose quickly and remained alkaline for approximately 4.5-7.5 h before returning to baseline. Although significantly different (p < 0.05), there was overlap between the fasted (153 +/- 87 min) and fed (436 +/- 265 (slurry) and 697 +/- 193 (standard) min) GRT due to considerable inter- and intra-subject variability. Fasted gastric pH was similar between monkeys and literature human values. After a meal, the monkey gastric pH was elevated for a longer duration than that in human. The monkey GRT appears longer than that observed in human under both fasted and fed conditions, although this is likely dependent on the Bravo capsule size.

Research paper thumbnail of MOESM3 of Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition

Additional file 3: Table S3a. Reactions for tumor signaling module. The reactions, rate equations... more Additional file 3: Table S3a. Reactions for tumor signaling module. The reactions, rate equations and parameters for the tumor signaling module. Unless otherwise specified, the reactions and rate constants were taken or modified from Zhang et al. [33], Kholodenko et al. [34], Sasagawa et al. [35]. Additions by the authors are superscripted with a, b, or c, respectively. Table S3b. Reactions for hypoxia signaling module. The reactions, rate equations and parameters for the hypoxia signaling module. The reactions and rate constants were taken or modified from Kohn et al. [32].

Research paper thumbnail of MOESM2 of Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition

Additional file 2: Table S2a. Initial values for species in the tumor signaling module [45, 46]. ... more Additional file 2: Table S2a. Initial values for species in the tumor signaling module [45, 46]. A table of species and initial concentrations for the tumor signaling module. Table S2b. Initial values for species in the hypoxia signaling module. A table of species and initial concentrations for the hypoxia signaling module.

Research paper thumbnail of MOESM1 of Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition

Additional file 1. Model description and simulation. This document contains additional informatio... more Additional file 1. Model description and simulation. This document contains additional information on model development, simulation, and analysis.

Research paper thumbnail of Content Alerts

This article cites 15 articles, 7 of which can be accessed free at:

Research paper thumbnail of Discovery of a Novel and Potent Class of FabI-Directed Antibacterial Agents

Antimicrobial Agents and Chemotherapy, 2002

Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elon... more Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus . Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [( E )- N -methyl- N -(2-methyl-1 H -indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and St...

Research paper thumbnail of A model for spatiotemporal frequency responses in the X cell pathway of the cat's retina

Vision Research, 1989

A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus... more A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus at the cornea, to cones, to X-type ganglion cells. The model contains elements representing the eye's optics, phototransduction, gain control, spatiotemporal processing by cell layers, and pure delay. Centresurround antagonism in the model arises through the presence of a centre element producing a small spatial spread of signals, and an antagonistic element producing a larger spread. Two arrangements were tried, feedforward and feedback, in which the antagonistic element's output was subtracted from the centre element's outptB, and input, respectively. The model was fitted to empirical spatial and temporal frequency responses collected by Frishman et al. (1987), and accounted qualitatively for these data in the feedback, but not the feedforward, arrangement. The model's centre pathway comprises a cascade of low-pass spatial filters, as does the surround pathway. As a consequence, the spatial frequency responses for these two pathways closely approximate Gaussian functions of spatial frequency, and the spatial frequency response of the complete model at low temporal frequency closely matches that of the difference of Gaussians model. Cat Retina Ganglion cell Spatial frequency Temporal frequency

Research paper thumbnail of Effects of Tricaine Methanesulfonate in a Managed Collection of Moon Jellyfish (Aurelia Aurita)

Journal of Zoo and Wildlife Medicine, 2022

Abstract: The moon jellyfish (Aurelia aurita) is a scyphozoan frequently maintained in public and... more Abstract: The moon jellyfish (Aurelia aurita) is a scyphozoan frequently maintained in public and private aquaria. Little research has been conducted to investigate the effects of various drugs, such as anesthetics, in this species. Tricaine methanesulfonate (MS-222), a common immersion anesthetic for fish and amphibians, was evaluated in a managed population of moon jellyfish. Twenty-four clinically healthy jellyfish were assigned into three groups of eight for trials of 0.3 g/L MS-222 (low concentration [LC]), 0.6 g/L MS-222 (high concentration [HC]), and a saltwater control. The goal was to evaluate the effects of MS-222 administration on moon jellyfish movement and response to stimuli. Movement and response to stimuli were measured via rocking and probe stimulus tests and observations of bell contraction quality and body tone. These tests were performed at baseline and throughout both drug exposure and recovery periods. A threshold drug effect was defined based on systematic scoring criteria. Additionally, elastomer tags were administered to four of eight animals in each MS-222 group to evaluate response to tag placement after drug exposure. Threshold drug effect was achieved in six of eight individuals in the LC group and eight of eight individuals in the HC group. The LC group had median threshold and recovery times of 12.2 and 10.1 min, respectively, while the HC group had median threshold and recovery times of 4.0 and 19.9 min, respectively. The HC group had significantly faster time to threshold drug effect (P < 0.001) and longer recovery times (P= 0.005) than the LC group. In both the LC and HC tagged group, three of four jellyfish had no reaction to tag placement. All animals recovered uneventfully, and there were no mortalities. MS-222 at 0.3 and 0.6 g/L decreased movement and response to stimuli in moon jellyfish.

Research paper thumbnail of Whole blood fatty acid concentrations in the San Cristóbal Galápagos tortoise (Chelonoidis chathamensis)

PeerJ, 2021

To continue releasing San Cristóbal Galápagos tortoises housed in managed-care facilities at the ... more To continue releasing San Cristóbal Galápagos tortoises housed in managed-care facilities at the Giant Tortoise Breeding Center of Galápagos National Park (Galapaguera de Cerro Colorado) to the Otoy Ecological Farm, health assessments and physical examinations were conducted. As a part of these wellness examinations, blood was drawn from 11 tortoises to analyze fatty acid concentrations. Fatty acid levels can provide insight into the nutritional profiles, immune status, and reproductive health of vertebrates. To the co-author’s knowledge, there is no current information about fatty acids in this species. It was hypothesized that there would be inherent differences based on the different geographic ranges, diets, sex, and age of turtles. It was noted that the ω-6/ω-3 ratio was higher for the breeding center than for the ecological farm and that overall polyunsaturated fatty acids (PUFAs) did not have any significant differences. The ω-6/ω-3 findings can contribute to a global picture...

Research paper thumbnail of Applications of the model-based target pharmacology assessment (mTPA) in defining drug design and DMPK strategies: GSK Experiences

Research paper thumbnail of Model-based Target Pharmacology Assessment (mTPA): An Approach Using PBPK/PD Modeling and Machine Learning to Design Medicinal Chemistry and DMPK Strategies in Early Drug Discovery

Journal of Medicinal Chemistry, 2021

The optimal pharmacokinetic (PK) required for a drug candidate to elicit efficacy is highly depen... more The optimal pharmacokinetic (PK) required for a drug candidate to elicit efficacy is highly dependent on the targeted pharmacology, a relationship that is often not well characterized during early phases of drug discovery. Generic assumptions around PK and potency risk misguiding screening and compound design toward nonoptimal absorption, distribution, metabolism, and excretion (ADME) or molecular properties and ultimately may increase attrition as well as hit-to-lead and lead optimization timelines. The present work introduces model-based target pharmacology assessment (mTPA), a computational approach combining physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling, sensitivity analysis, and machine learning (ML) to elucidate the optimal combination of PK, potency, and ADME specific for the targeted pharmacology. Examples using frequently encountered PK/PD relationships are presented to illustrate its application, and the utility and benefits of deploying such an approach to guide early discovery efforts are discussed.

Research paper thumbnail of Field-Based Radiographic Imaging of Marine Megafauna: Marine Iguanas (Amblyrhynchus cristatus) as a Case Study

Frontiers in Marine Science, 2018

Effective conservation of marine megafauna requires a thorough understanding of the ecology, phys... more Effective conservation of marine megafauna requires a thorough understanding of the ecology, physiology, population dynamics, and health of vulnerable species. Assessing the health of large, mobile marine animals poses particular challenges, in part because the subjects are difficult to capture and restrain, and in part because standard laboratory and diagnostic tools are difficult to apply in a field setting. Radiography is a critically important diagnostic tool used routinely by veterinarians, but it has seldom been possible to image live marine vertebrates in the field. As a first step toward assessing the feasibility of incorporating radiography into studies of vulnerable species in remote locations, we used portable radiographic equipment to acquire the first digital internal images of living marine iguanas, Amblyrhynchus cristatus, an iconic lizard endemic only to the Galápagos Islands of Ecuador. The radiographic machinery was powered by batteries and performed well on a rocky beach environment of an uninhabited island, despite high heat and humidity. The accuracy of radiographic measurements was validated by computing a snout-vent length (SVL) using bone dimensions and comparing this to standard measurements of SVL made externally with a tape measure. These results demonstrate the feasibility of using radiography to study animals in remote sites, a technique that may prove useful for a variety of physiological, ecological, and biomechanical studies in which reliable measurements of skeletal and soft-tissue dimensions must be acquired under challenging field conditions. Refinements are discussed that will help the technology reach its full potential in field studies.

Research paper thumbnail of Temporal Patterns in Admission of Eastern Box Turtles (Terrapene Carolina Carolina) at a North Carolina Wildlife Clinic as a Reflection of Climate

Journal of Zoo and Wildlife Medicine, 2020

Abstract: Significant impacts of global climate change on wildlife have been documented and are p... more Abstract: Significant impacts of global climate change on wildlife have been documented and are projected to continue. Reptiles have been suggested as being especially susceptible to these effects along with other anthropogenic impacts on their environment. A retrospective review of medical records for 2,356 wild eastern box turtles (Terrapene carolina carolina) admitted to the Turtle Rescue Team (TRT) at the North Carolina State University College of Veterinary Medicine between 1996 and 2017 was performed in order to: 1) report common presenting complaints, 2) describe the timeline of when box turtles were admitted to the TRT for each year of the study, and 3) investigate temporal shifts in turtle admissions and associations with changes in environmental temperature over a 22-yr period. The most common presenting complaint was vehicular trauma (n = 1,195) with over 70% of the caseload associated with anthropogenic impacts. Average monthly temperatures from 1996 to 2017 for Raleigh, North Carolina, USA, were extracted from the National Oceanic and Atmospheric Administration climate database. By comparing the pre- and post-2006 years using the Mann–Whitney test, we found that both the annual peak temperature and the annual timing of admission to the TRT have shifted significantly or with a strong tendency towards significance (P = 0.0008 and 0.052, respectively). Annual peak temperature has increased by 1.3°C, and timing of admission has shifted 18 days earlier between pre- and post-2006 years. This supports the hypothesis that box turtle activity patterns are shifting and that these changes are potentially related to climate.

Research paper thumbnail of Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition

BMC Bioinformatics, 2019

Background Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and signif... more Background Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and significant cell-to-cell variability. Due to the complexity of the disease, the explanation of why anticancer therapies fail cannot be attributed to intrinsic or acquired drug resistance alone. Furthermore, there are inconsistent reports of hypoxia-induced kinase activities in different cancer cell-lines, where increase, decreases, or no change has been observed. Thus, we asked, why are there widely contrasting results in kinase activity under hypoxia in different cancer cell-lines and how does hypoxia play a role in anti-cancer drug sensitivity? Results We took a modeling approach to address these questions by analyzing the model simulation to explain why hypoxia driven signals can have dissimilar impact on tumor growth and alter the efficacy of anti-cancer drugs. Repeated simulations with varying concentrations of biomolecules followed by decision tree analysis reveal that the highly differe...

Research paper thumbnail of Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism

British journal of cancer, Jan 27, 2010

Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerat... more Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction. Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study. No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (P<0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotyp...

Research paper thumbnail of Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer

Xenobiotica, 2012

1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the t... more 1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. 2. In this two-part study, we investigated the metabolism, disposition of [(14)C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer. 3. In part A, three men each received a single oral dose of [(14)C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose). 4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5-28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%.

Research paper thumbnail of Differences in Effects on Myocardium and Mitochondria by Angiogenic Inhibitors Suggest Separate Mechanisms of Cardiotoxicity

Toxicologic Pathology, 2010

Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxic... more Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxicity, suggesting an on-target pharmacologic effect. To evaluate whether cardiotoxicity is directly related to vascular endothelial growth factor receptor inhibition, we investigated the effects of sunitinib, sorafenib, and pazopanib on myocardial function and structure. We used a rat model to assess myocardial effects of the inhibitors concurrently exposed to the cardiac stressor dobutamine. Echocardiographic abnormalities including premature ventricular contractions, decreases in heart rate, circumferential strain, and radial and circumferential strain rates were noted with sorafenib, but not with sunitinib or pazopanib. Ultrastructural analysis of ventricular cardiomyocytes by transmission electron microscopy revealed mitochondrial swelling, dense deposits, and matrix cavitation in rats given sunitinib and disrupted mitochondrial cristae in rats given sorafenib, but there were no effect...

Research paper thumbnail of Model-Based Virtual PK/PD Exploration and Machine Learning Approach to Define PK Drivers in Early Drug Discovery

Journal of medicinal chemistry, Feb 20, 2024

Research paper thumbnail of A model for spatiotemporal frequency responses in the X cell pathway of the cat's retina

Vision Research, 1989

A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus... more A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus at the cornea, to cones, to X-type ganglion cells. The model contains elements representing the eye's optics, phototransduction, gain control, spatiotemporal processing by cell layers, and pure delay. Centresurround antagonism in the model arises through the presence of a centre element producing a small spatial spread of signals, and an antagonistic element producing a larger spread. Two arrangements were tried, feedforward and feedback, in which the antagonistic element's output was subtracted from the centre element's outptB, and input, respectively. The model was fitted to empirical spatial and temporal frequency responses collected by Frishman et al. (1987), and accounted qualitatively for these data in the feedback, but not the feedforward, arrangement. The model's centre pathway comprises a cascade of low-pass spatial filters, as does the surround pathway. As a consequence, the spatial frequency responses for these two pathways closely approximate Gaussian functions of spatial frequency, and the spatial frequency response of the complete model at low temporal frequency closely matches that of the difference of Gaussians model. Cat Retina Ganglion cell Spatial frequency Temporal frequency

Research paper thumbnail of Applications of Model-Based Target Pharmacology Assessment in Defining Drug Design and DMPK Strategies: GSK Experiences

Journal of Medicinal Chemistry, May 2, 2022

Research paper thumbnail of Gastric pH and Gastric Residence Time in Fasted and Fed Conscious Cynomolgus Monkeys Using the Bravo® pH System

Pharmaceutical Research, Jul 6, 2007

To measure fasted and fed gastric pH and gastric residence time (GRT) in Cynomolgus monkeys using... more To measure fasted and fed gastric pH and gastric residence time (GRT) in Cynomolgus monkeys using Bravo radiotelemetry capsules. Continuous pH measurements were recorded with Bravo capsules, which were either attached to the monkeys&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; stomach or administered as free capsules. Meals (either slurry or standard), were administered at designated times with monkeys chair-restrained during slurry meal ingestion. From the attached capsule studies, the fasted gastric pH (~1.9-2.2) was consistent among monkeys. Under fasted conditions, pH spikes were infrequently observed (once every 7.9 min to 3.6 h) with peaks reaching pH 9.4 and having short durations (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1 min). After feeding, the gastric pH rose quickly and remained alkaline for approximately 4.5-7.5 h before returning to baseline. Although significantly different (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), there was overlap between the fasted (153 +/- 87 min) and fed (436 +/- 265 (slurry) and 697 +/- 193 (standard) min) GRT due to considerable inter- and intra-subject variability. Fasted gastric pH was similar between monkeys and literature human values. After a meal, the monkey gastric pH was elevated for a longer duration than that in human. The monkey GRT appears longer than that observed in human under both fasted and fed conditions, although this is likely dependent on the Bravo capsule size.

Research paper thumbnail of MOESM3 of Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition

Additional file 3: Table S3a. Reactions for tumor signaling module. The reactions, rate equations... more Additional file 3: Table S3a. Reactions for tumor signaling module. The reactions, rate equations and parameters for the tumor signaling module. Unless otherwise specified, the reactions and rate constants were taken or modified from Zhang et al. [33], Kholodenko et al. [34], Sasagawa et al. [35]. Additions by the authors are superscripted with a, b, or c, respectively. Table S3b. Reactions for hypoxia signaling module. The reactions, rate equations and parameters for the hypoxia signaling module. The reactions and rate constants were taken or modified from Kohn et al. [32].

Research paper thumbnail of MOESM2 of Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition

Additional file 2: Table S2a. Initial values for species in the tumor signaling module [45, 46]. ... more Additional file 2: Table S2a. Initial values for species in the tumor signaling module [45, 46]. A table of species and initial concentrations for the tumor signaling module. Table S2b. Initial values for species in the hypoxia signaling module. A table of species and initial concentrations for the hypoxia signaling module.

Research paper thumbnail of MOESM1 of Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition

Additional file 1. Model description and simulation. This document contains additional informatio... more Additional file 1. Model description and simulation. This document contains additional information on model development, simulation, and analysis.

Research paper thumbnail of Content Alerts

This article cites 15 articles, 7 of which can be accessed free at:

Research paper thumbnail of Discovery of a Novel and Potent Class of FabI-Directed Antibacterial Agents

Antimicrobial Agents and Chemotherapy, 2002

Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elon... more Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus . Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [( E )- N -methyl- N -(2-methyl-1 H -indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and St...

Research paper thumbnail of A model for spatiotemporal frequency responses in the X cell pathway of the cat's retina

Vision Research, 1989

A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus... more A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus at the cornea, to cones, to X-type ganglion cells. The model contains elements representing the eye's optics, phototransduction, gain control, spatiotemporal processing by cell layers, and pure delay. Centresurround antagonism in the model arises through the presence of a centre element producing a small spatial spread of signals, and an antagonistic element producing a larger spread. Two arrangements were tried, feedforward and feedback, in which the antagonistic element's output was subtracted from the centre element's outptB, and input, respectively. The model was fitted to empirical spatial and temporal frequency responses collected by Frishman et al. (1987), and accounted qualitatively for these data in the feedback, but not the feedforward, arrangement. The model's centre pathway comprises a cascade of low-pass spatial filters, as does the surround pathway. As a consequence, the spatial frequency responses for these two pathways closely approximate Gaussian functions of spatial frequency, and the spatial frequency response of the complete model at low temporal frequency closely matches that of the difference of Gaussians model. Cat Retina Ganglion cell Spatial frequency Temporal frequency

Research paper thumbnail of Effects of Tricaine Methanesulfonate in a Managed Collection of Moon Jellyfish (Aurelia Aurita)

Journal of Zoo and Wildlife Medicine, 2022

Abstract: The moon jellyfish (Aurelia aurita) is a scyphozoan frequently maintained in public and... more Abstract: The moon jellyfish (Aurelia aurita) is a scyphozoan frequently maintained in public and private aquaria. Little research has been conducted to investigate the effects of various drugs, such as anesthetics, in this species. Tricaine methanesulfonate (MS-222), a common immersion anesthetic for fish and amphibians, was evaluated in a managed population of moon jellyfish. Twenty-four clinically healthy jellyfish were assigned into three groups of eight for trials of 0.3 g/L MS-222 (low concentration [LC]), 0.6 g/L MS-222 (high concentration [HC]), and a saltwater control. The goal was to evaluate the effects of MS-222 administration on moon jellyfish movement and response to stimuli. Movement and response to stimuli were measured via rocking and probe stimulus tests and observations of bell contraction quality and body tone. These tests were performed at baseline and throughout both drug exposure and recovery periods. A threshold drug effect was defined based on systematic scoring criteria. Additionally, elastomer tags were administered to four of eight animals in each MS-222 group to evaluate response to tag placement after drug exposure. Threshold drug effect was achieved in six of eight individuals in the LC group and eight of eight individuals in the HC group. The LC group had median threshold and recovery times of 12.2 and 10.1 min, respectively, while the HC group had median threshold and recovery times of 4.0 and 19.9 min, respectively. The HC group had significantly faster time to threshold drug effect (P < 0.001) and longer recovery times (P= 0.005) than the LC group. In both the LC and HC tagged group, three of four jellyfish had no reaction to tag placement. All animals recovered uneventfully, and there were no mortalities. MS-222 at 0.3 and 0.6 g/L decreased movement and response to stimuli in moon jellyfish.

Research paper thumbnail of Whole blood fatty acid concentrations in the San Cristóbal Galápagos tortoise (Chelonoidis chathamensis)

PeerJ, 2021

To continue releasing San Cristóbal Galápagos tortoises housed in managed-care facilities at the ... more To continue releasing San Cristóbal Galápagos tortoises housed in managed-care facilities at the Giant Tortoise Breeding Center of Galápagos National Park (Galapaguera de Cerro Colorado) to the Otoy Ecological Farm, health assessments and physical examinations were conducted. As a part of these wellness examinations, blood was drawn from 11 tortoises to analyze fatty acid concentrations. Fatty acid levels can provide insight into the nutritional profiles, immune status, and reproductive health of vertebrates. To the co-author’s knowledge, there is no current information about fatty acids in this species. It was hypothesized that there would be inherent differences based on the different geographic ranges, diets, sex, and age of turtles. It was noted that the ω-6/ω-3 ratio was higher for the breeding center than for the ecological farm and that overall polyunsaturated fatty acids (PUFAs) did not have any significant differences. The ω-6/ω-3 findings can contribute to a global picture...

Research paper thumbnail of Applications of the model-based target pharmacology assessment (mTPA) in defining drug design and DMPK strategies: GSK Experiences

Research paper thumbnail of Model-based Target Pharmacology Assessment (mTPA): An Approach Using PBPK/PD Modeling and Machine Learning to Design Medicinal Chemistry and DMPK Strategies in Early Drug Discovery

Journal of Medicinal Chemistry, 2021

The optimal pharmacokinetic (PK) required for a drug candidate to elicit efficacy is highly depen... more The optimal pharmacokinetic (PK) required for a drug candidate to elicit efficacy is highly dependent on the targeted pharmacology, a relationship that is often not well characterized during early phases of drug discovery. Generic assumptions around PK and potency risk misguiding screening and compound design toward nonoptimal absorption, distribution, metabolism, and excretion (ADME) or molecular properties and ultimately may increase attrition as well as hit-to-lead and lead optimization timelines. The present work introduces model-based target pharmacology assessment (mTPA), a computational approach combining physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling, sensitivity analysis, and machine learning (ML) to elucidate the optimal combination of PK, potency, and ADME specific for the targeted pharmacology. Examples using frequently encountered PK/PD relationships are presented to illustrate its application, and the utility and benefits of deploying such an approach to guide early discovery efforts are discussed.

Research paper thumbnail of Field-Based Radiographic Imaging of Marine Megafauna: Marine Iguanas (Amblyrhynchus cristatus) as a Case Study

Frontiers in Marine Science, 2018

Effective conservation of marine megafauna requires a thorough understanding of the ecology, phys... more Effective conservation of marine megafauna requires a thorough understanding of the ecology, physiology, population dynamics, and health of vulnerable species. Assessing the health of large, mobile marine animals poses particular challenges, in part because the subjects are difficult to capture and restrain, and in part because standard laboratory and diagnostic tools are difficult to apply in a field setting. Radiography is a critically important diagnostic tool used routinely by veterinarians, but it has seldom been possible to image live marine vertebrates in the field. As a first step toward assessing the feasibility of incorporating radiography into studies of vulnerable species in remote locations, we used portable radiographic equipment to acquire the first digital internal images of living marine iguanas, Amblyrhynchus cristatus, an iconic lizard endemic only to the Galápagos Islands of Ecuador. The radiographic machinery was powered by batteries and performed well on a rocky beach environment of an uninhabited island, despite high heat and humidity. The accuracy of radiographic measurements was validated by computing a snout-vent length (SVL) using bone dimensions and comparing this to standard measurements of SVL made externally with a tape measure. These results demonstrate the feasibility of using radiography to study animals in remote sites, a technique that may prove useful for a variety of physiological, ecological, and biomechanical studies in which reliable measurements of skeletal and soft-tissue dimensions must be acquired under challenging field conditions. Refinements are discussed that will help the technology reach its full potential in field studies.

Research paper thumbnail of Temporal Patterns in Admission of Eastern Box Turtles (Terrapene Carolina Carolina) at a North Carolina Wildlife Clinic as a Reflection of Climate

Journal of Zoo and Wildlife Medicine, 2020

Abstract: Significant impacts of global climate change on wildlife have been documented and are p... more Abstract: Significant impacts of global climate change on wildlife have been documented and are projected to continue. Reptiles have been suggested as being especially susceptible to these effects along with other anthropogenic impacts on their environment. A retrospective review of medical records for 2,356 wild eastern box turtles (Terrapene carolina carolina) admitted to the Turtle Rescue Team (TRT) at the North Carolina State University College of Veterinary Medicine between 1996 and 2017 was performed in order to: 1) report common presenting complaints, 2) describe the timeline of when box turtles were admitted to the TRT for each year of the study, and 3) investigate temporal shifts in turtle admissions and associations with changes in environmental temperature over a 22-yr period. The most common presenting complaint was vehicular trauma (n = 1,195) with over 70% of the caseload associated with anthropogenic impacts. Average monthly temperatures from 1996 to 2017 for Raleigh, North Carolina, USA, were extracted from the National Oceanic and Atmospheric Administration climate database. By comparing the pre- and post-2006 years using the Mann–Whitney test, we found that both the annual peak temperature and the annual timing of admission to the TRT have shifted significantly or with a strong tendency towards significance (P = 0.0008 and 0.052, respectively). Annual peak temperature has increased by 1.3°C, and timing of admission has shifted 18 days earlier between pre- and post-2006 years. This supports the hypothesis that box turtle activity patterns are shifting and that these changes are potentially related to climate.

Research paper thumbnail of Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition

BMC Bioinformatics, 2019

Background Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and signif... more Background Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and significant cell-to-cell variability. Due to the complexity of the disease, the explanation of why anticancer therapies fail cannot be attributed to intrinsic or acquired drug resistance alone. Furthermore, there are inconsistent reports of hypoxia-induced kinase activities in different cancer cell-lines, where increase, decreases, or no change has been observed. Thus, we asked, why are there widely contrasting results in kinase activity under hypoxia in different cancer cell-lines and how does hypoxia play a role in anti-cancer drug sensitivity? Results We took a modeling approach to address these questions by analyzing the model simulation to explain why hypoxia driven signals can have dissimilar impact on tumor growth and alter the efficacy of anti-cancer drugs. Repeated simulations with varying concentrations of biomolecules followed by decision tree analysis reveal that the highly differe...

Research paper thumbnail of Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism

British journal of cancer, Jan 27, 2010

Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerat... more Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction. Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study. No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (P<0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotyp...

Research paper thumbnail of Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer

Xenobiotica, 2012

1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the t... more 1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. 2. In this two-part study, we investigated the metabolism, disposition of [(14)C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer. 3. In part A, three men each received a single oral dose of [(14)C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose). 4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5-28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%.

Research paper thumbnail of Differences in Effects on Myocardium and Mitochondria by Angiogenic Inhibitors Suggest Separate Mechanisms of Cardiotoxicity

Toxicologic Pathology, 2010

Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxic... more Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxicity, suggesting an on-target pharmacologic effect. To evaluate whether cardiotoxicity is directly related to vascular endothelial growth factor receptor inhibition, we investigated the effects of sunitinib, sorafenib, and pazopanib on myocardial function and structure. We used a rat model to assess myocardial effects of the inhibitors concurrently exposed to the cardiac stressor dobutamine. Echocardiographic abnormalities including premature ventricular contractions, decreases in heart rate, circumferential strain, and radial and circumferential strain rates were noted with sorafenib, but not with sunitinib or pazopanib. Ultrastructural analysis of ventricular cardiomyocytes by transmission electron microscopy revealed mitochondrial swelling, dense deposits, and matrix cavitation in rats given sunitinib and disrupted mitochondrial cristae in rats given sorafenib, but there were no effect...