Meta-Analysis of Exposure-Adverse Event Relationships for Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) have become a vital class of therapeutics in oncology because of their ability to selectively deliver potent drug molecules to tumor cells. However, ADC-associated toxicities cause high failure rates in the clinic and hinder their full potential. Due to the complex structure and pharmacokinetics of ADCs, it is challenging to identify the drivers of their toxicities.

Multiscale computational model of aortic remodeling following postnatal disruption of TGFβ signaling.

The healthy adult aorta is a remarkably resilient structure, able to resist relentless cardiac-induced and hemodynamic loads under normal conditions. Fundamental to such mechanical homeostasis is the mechano-sensitive cell signaling that controls gene products and thus the structural integrity of the wall. Mouse models have shown that smooth muscle cell-specific disruption of transforming growth factor-beta (TGFβ) signaling during postnatal development compromises this resiliency, rendering the aortic wall susceptible to aneurysm and dissection under normal mechanical loading.

Physiological Indirect Response Model to Omics-Powered Quantitative Systems Pharmacology Model.

Over the past several decades, mathematical modeling has been applied to increasingly wider scopes of questions in drug development. Accordingly, the range of modeling tools has also been evolving, as showcased by contributions of Jusko and colleagues: from basic pharmacokinetics/pharmacodynamics (PK/PD) modeling to today's platform-based approach of quantitative systems pharmacology (QSP) modeling. Aimed at understanding the mechanism of action of investigational drugs, QSP models characterize systemic effects by incorporating information about cellular signaling networks, which is often represented by omics data.

Persistent non-homeostatic remodeling of aortic collagen following a brief episode of hypertension: A computational study.

The healthy adult aorta exhibits a remarkable homeostatic ability to respond to sustained changes in hemodynamic loads under many circumstances, but this mechanical homeostasis can be compromised or lost in natural aging and diverse pathological processes. Herein, we investigate persistent non-homeostatic changes in the composition and mechanical properties of the thoracic aorta in adult wild-type mice following 14 days of angiotensin II-induced hypertension. We employ a multiscale computational model of arterial growth and remodeling driven by mechanosensitive and angiotensin II-related cell signaling pathways.

Intracellular signaling control of mechanical homeostasis in the aorta.

Mature arteries exhibit a preferred biomechanical state in health evidenced by a narrow range of intramural and wall shear stresses. When stresses are perturbed by changes in blood pressure or flow, homeostatic mechanisms tend to restore target values via altered contractility and/or cell and matrix turnover. In contrast, vascular disease associates with compromised homeostasis, hence we must understand mechanisms underlying mechanical homeostasis and its robustness.