Development of and insights from systems pharmacology models of antibody-drug conjugates.

Antibody-drug conjugates (ADCs) have gained traction in the oncology space in the past few decades, with significant progress being made in recent years. Although the use of pharmacometric modeling is well-established in the drug development process, there is an increasing need for a better quantitative biological understanding of the pharmacokinetic and pharmacodynamic relationships of these complex molecules. Quantitative systems pharmacology (QSP) approaches can assist in this endeavor; recent computational QSP models incorporate ADC-specific mechanisms and use data-driven simulations to predict experimental outcomes. Various modeling approaches and platforms have been developed at the in vitro, in vivo, and clinical scales, and can be further integrated to facilitate preclinical to clinical translation. These new tools can help researchers better understand the nature and mechanisms of these targeted therapies to help achieve a more favorable therapeutic window. This review delves into the world of systems pharmacology modeling of ADCs, discussing various modeling efforts in the field thus far.

An mHealth App (Speech Banana) for Auditory Training: App Design and Development Study.

BACKGROUND: With the growing adult population using electronic hearing devices such as cochlear implants or hearing aids, there is an increasing worldwide need for auditory training (AT) to promote optimal device use. However, financial resources and scheduling conflicts make clinical AT infeasible. OBJECTIVE: To address this gap between need and accessibility, we primarily aimed to develop a mobile health (mHealth) app called Speech Banana for AT. The app would be substantially more affordable and portable than clinical AT; would deliver a validated training model that is reflective of modern techniques; and would track users' progress in speech comprehension, providing greater continuity between periodic in-person visits. To improve international availability, our secondary aim was to implement the English language training model into Korean as a proof of concept for worldwide usability. METHODS: A problem- and objective-centered Design Science Research Methodology approach was adopted to develop the Speech Banana app. A review of previous literature and computer-based learning programs outlined current AT gaps, whereas interviews with speech pathologists and users clarified the features that were addressed in the app. Past and present users were invited to evaluate the app via community forums and the System Usability Scale. RESULTS: Speech Banana has been implemented in English and Korean languages for iPad and web use. The app comprises 38 lessons, which include analytic exercises pairing visual and auditory stimuli, and synthetic quizzes presenting auditory stimuli only. During quizzes, users type the sentence heard, and the app provides visual feedback on performance. Users may select a male or female speaker and the volume of background noise, allowing for training with a range of frequencies and signal-to-noise ratios. There were more than 3200 downloads of the English iPad app and almost 100 downloads of the Korean app; more than 100 users registered for the web apps. The English app received a System Usability Scale rating of "good" from 6 users, and the Korean app received a rating of "OK" from 16 users. CONCLUSIONS: Speech Banana offers AT accessibility with a validated curriculum, allowing users to develop speech comprehension skills with the aid of a mobile device. This mHealth app holds potential as a supplement to clinical AT, particularly in this era of global telemedicine.

Context-dependent regulation of receptor tyrosine kinases: Insights from systems biology approaches.

Receptor tyrosine kinases (RTKs) are cell membrane proteins that provide cells with the ability to sense proteins in their environments. Many RTKs are essential to development and organ growth. Derangement of RTKs-by mutation or by overexpression-is central to several developmental and adult disorders including cancer, short stature, and vascular pathologies. The mechanism of action of RTKs is complex and is regulated by contextual components, including the existence of multiple competing ligands and receptors in many families, the intracellular location of the RTK, the dynamic and cell-specific coexpression of other RTKs, and the commonality of downstream signaling pathways. This means that both the state of the cell and the microenvironment outside the cell play a role, which makes sense given the pivotal location of RTKs as the nexus linking the extracellular milieu to intracellular signaling and modification of cell behavior. In this review, we describe these different contextual components through the lens of systems biology, in which both computational modeling and experimental "omics" approaches have been used to better understand RTK networks. The complexity of these networks is such that using these systems biology approaches is necessary to get a handle on the mechanisms of pathology and the design of therapeutics targeting RTKs. In particular, we describe in detail three concrete examples (involving ErbB3, VEGFR2, and AXL) that illustrate how systems approaches can reveal key mechanistic and therapeutic insights. This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models Translational, Genomic, and Systems Medicine > Therapeutic Methods.