Serum AZD7442 (tixagevimab-cilgavimab) concentrations and IC values predict SARS-CoV-2 neutralising antibody titres.

Objectives: The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates rapid methods for assessing monoclonal antibody (mAb) potency against emerging variants. Authentic virus neutralisation assays are considered the gold standard for measuring virus-neutralising antibody (nAb) titres in serum. However, authentic virus-based assays pose inherent practical challenges for measuring nAb titres against emerging SARS-CoV-2 variants (e.

Potassium homeostasis and therapeutic intervention with sodium zirconium cyclosilicate: A model-informed drug development case study.

Potassium (K ) is the main intracellular cation in the body. Elevated K levels (hyperkalemia) increase the risk of life-threatening arrhythmias and sudden cardiac death. However, the details of K homeostasis and the effects of orally administered K binders, such as sodium zirconium cyclosilicate (SZC), on K redistribution and excretion in patients remain incompletely understood.

Assessing reproducibility and utility of clustering of patients with type 2 diabetes and established CV disease (SAVOR -TIMI 53 trial).

Objective: To assess the reproducibility and clinical utility of clustering-based subtyping of patients with type 2 diabetes (T2D) and established cardiovascular (CV) disease.

Methods: The cardiovascular outcome trial SAVOR-TIMI 53 (n = 16,492) was used. Analyses focused on T2D patients with established CV disease.

Cardiovascular and renal safety of metformin in patients with diabetes and moderate or severe chronic kidney disease: Observations from the EXSCEL and SAVOR-TIMI 53 cardiovascular outcomes trials.

Aim: To provide evidence on the cardiovascular and renal safety of metformin in chronic kidney disease (CKD) stages 3 to 4.

Materials And Methods: This post hoc analysis compared participants with an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73m in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) and the Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (SAVOR-TIMI 53) trials taking metformin, with those not exposed to metformin during these trials, using a propensity-matching approach.

Effect of once-weekly exenatide on estimated glomerular filtration rate slope depends on baseline renal risk: A post hoc analysis of the EXSCEL trial.

The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on renal outcomes in patients with type 2 diabetes at high cardiovascular risk are modest or neutral. However, GLP-1RAs may confer clinical benefits in those at high risk of progressive renal function loss. We examined the effects of once-weekly exenatide (EQW) on estimated glomerular filtration rate (eGFR) slope and urinary albumin:creatinine ratio (UACR) as a function of baseline UACR in 3503 EXSCEL participants (23.

Prediction and validation of exenatide risk marker effects on progression of renal disease: Insights from EXSCEL.

Aim: To assess whether the previously developed multivariable risk prediction framework (PRE score) could predict the renal effects observed in the EXSCEL cardiovascular outcomes trial using short-term changes in cardio-renal risk markers.

Materials And Methods: Changes from baseline to 6 months in HbA1c, systolic blood pressure (SBP), body mass index (BMI), haemoglobin, total cholesterol, and new micro- or macroalbuminuria were evaluated. The renal outcomes were defined as a composite of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD).

Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes.

Reduction of Cardiovascular Risk and Improved Estimated Glomerular Filtration Rate by SGLT2 Inhibitors, Including Dapagliflozin, Is Consistent Across the Class: An Analysis of the Placebo Arm of EXSCEL.

Objective: The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole.

Research Design And Methods: SGLT2i drop-in therapy occurred in 10.

A computational analysis of pro-angiogenic therapies for peripheral artery disease.

Inducing therapeutic angiogenesis to effectively form hierarchical, non-leaky networks of perfused vessels in tissue engineering applications and ischemic disease remains an unmet challenge, despite extensive research and multiple clinical trials. Here, we use a previously-developed, multi-scale, computational systems pharmacology model of human peripheral artery disease to screen a diverse array of promising pro-angiogenic strategies, including gene therapy, biomaterials, and antibodies. Our previously-validated model explicitly accounts for VEGF immobilization, Neuropilin-1 binding, and weak activation of VEGF receptor 2 (VEGFR2) by the "VEGF" isoforms.

Arterialized collateral capillaries progress from nonreactive to capable of increasing perfusion in an ischemic arteriolar tree.

Objective: CCA, outward remodeling of capillaries that anastomose 2 arteriolar trees with different parent feed arteries, may represent a therapeutic target for patients who lack collaterals. ACCs can reperfuse an ischemic tree, but their functional capacity is unknown. Therefore, we determined whether ACCs mature into resistance vessels that regulate blood flow following arterial occlusion.

Systems Pharmacology of VEGF165b in Peripheral Artery Disease.

We built a whole-body computational model to study the role of the poorly understood vascular endothelial growth factor (VEGF) splice isoform in peripheral artery disease (PAD). This model was built and validated using published and new experimental data from cells, mice, and humans, and explicitly accounts for known properties of VEGF : lack of extracellular matrix (ECM)-binding and weak phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR2) in vitro. The resulting model captures all known information about VEGF distribution and signaling in human PAD, and provides novel, nonintuitive insight into VEGF mechanism of action in vivo.

A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands.

The splice isoforms of vascular endothelial growth A (VEGF) each have different affinities for the extracellular matrix (ECM) and the coreceptor NRP1, which leads to distinct vascular phenotypes in model systems expressing only a single VEGF isoform. ECM-immobilized VEGF can bind to and activate VEGF receptor 2 (VEGFR2) directly, with a different pattern of site-specific phosphorylation than diffusible VEGF. To date, the way in which ECM binding alters the distribution of isoforms of VEGF and of the related placental growth factor (PlGF) in the body and resulting angiogenic signaling is not well-understood.

Further Support for ECM Control of Receptor Trafficking and Signaling.

Recently, Sack et al. (2016) presented an interesting, novel data set in Journal of Cellular Physiology examining the effect of substrate stiffness on VEGF processing and signaling. The data represent a clear contribution to the field.

Molecular mechanism matters: Benefits of mechanistic computational models for drug development.

Making drug development a more efficient and cost-effective process will have a transformative effect on human health. A key, yet underutilized, tool to aid in this transformation is mechanistic computational modeling. By incorporating decades of hard-won prior knowledge of molecular interactions, cellular signaling, and cellular behavior, mechanistic models can achieve a level of predictiveness that is not feasible using solely empirical characterization of drug pharmacodynamics.

Site-Specific Phosphorylation of VEGFR2 Is Mediated by Receptor Trafficking: Insights from a Computational Model.

Matrix-binding isoforms and non-matrix-binding isoforms of vascular endothelial growth factor (VEGF) are both capable of stimulating vascular remodeling, but the resulting blood vessel networks are structurally and functionally different. Here, we develop and validate a computational model of the binding of soluble and immobilized ligands to VEGF receptor 2 (VEGFR2), the endosomal trafficking of VEGFR2, and site-specific VEGFR2 tyrosine phosphorylation to study differences in induced signaling between these VEGF isoforms. In capturing essential features of VEGFR2 signaling and trafficking, our model suggests that VEGFR2 trafficking parameters are largely consistent across multiple endothelial cell lines.

Systems biology of the microvasculature.

The vascular network carries blood throughout the body, delivering oxygen to tissues and providing a pathway for communication between distant organs. The network is hierarchical and structured, but also dynamic, especially at the smaller scales. Remodeling of the microvasculature occurs in response to local changes in oxygen, gene expression, cell-cell communication, and chemical and mechanical stimuli from the microenvironment.