Pharmacometrics-based decision tools facilitate mHealth implementation.

The healthcare system is experiencing a paradigm shift in delivering its services, evolving from a reactive 'one size-fits-all' structure to a patient-centric model focusing on individualized medicine. This change is driven by scientific progress, including quantitative evaluation and optimization of treatment strategies through pharmacometric approaches, harnessing the power of the digital revolution. Areas covered: This review describes four main steps to apply pharmacometrics-based decision support tools, consisting of validated scientific components, available technical options, consideration of regulatory aspects, and achievement of efficient commercialization. Examples of pharmacometrics-based decision tools that support monitoring of patients and individualization of treatment strategies in neonates, children and adults are presented. Expert commentary: We envision that user-friendly decision support tools will facilitate implementation of mobile health approaches (mHealth) realizing benefits to paediatric and adult patients and their caregivers

Tristetraprolin (ZFP36) and TIS11B (ZFP36-L1)

International audienc

AMPK promotes tolerance to Ras pathway inhibition by activating autophagy

Targeted inhibitors of oncogenic Ras (rat sarcoma viral oncogene)-Raf signaling have shown great promise in the clinic, but resistance remains a major challenge: 30% of tumors with pathway mutations do not respond to targeted inhibitors, and of the 70% that do respond, all eventually develop resistance. Before cancer cells acquire resistance, they respond to initial drug treatment either by undergoing apoptosis ('addiction') or by surviving treatment albeit with reduced growth ('tolerance'). As these drug-tolerant cells serve as a reservoir from which resistant cells eventually emerge, inhibiting the pathways that confer tolerance could potentially delay or even prevent recurrence. Here, we show that melanomas and other cancers acquire tolerance to Ras-Raf pathway inhibitors by activating autophagy, which is mediated by the cellular energy sensor AMP-activated protein kinase (AMPK). Blocking this AMPK-mediated autophagy sensitizes drug-tolerant melanomas to Ras-Raf pathway inhibitors. Conversely, activating AMPK signaling and autophagy enables melanomas that would otherwise be addicted to the Ras-Raf pathway to instead tolerate pathway inhibition. These findings identify a key mechanism of tolerance to Ras-Raf pathway inhibitors and suggest that blocking either AMPK or autophagy in combination with these targeted inhibitors could increase tumor regression and decrease the likelihood of eventual recurrence.Melanoma Research Alliance (Grant 311800