YWHAG Deficiency Disrupts the EMT-Associated Network to Induce Oxidative Cell Death and Prevent Metastasis.

Metastasis involves epithelial-to-mesenchymal transition (EMT), a process that is regulated by complex gene networks, where their deliberate disruption may yield a promising outcome. However, little is known about mechanisms that coordinate these metastasis-associated networks. To address this gap, hub genes with broad engagement across various human cancers by analyzing the transcriptomes of different cancer cell types undergoing EMT are identified. The oncogenic signaling adaptor protein tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) is ranked top for its clinical relevance and impact. The cellular kinome and transcriptome data are surveyed to construct the regulome of YWHAG, revealing stress responses and metabolic processes during cancer EMT. It is demonstrated that a YWHAG-dependent cytoprotective mechanism in the regulome is embedded in EMT-associated networks to protect cancer cells from oxidative catastrophe through enhanced autophagy during EMT. YWHAG deficiency results in a rapid accumulation of reactive oxygen species (ROS), delayed EMT, and cell death. Tumor allografts show that metastasis potential and overall survival time are correlated with the YWHAG expression level of cancer cell lines. Metastasized tumors have higher expression of YWHAG and autophagy-related genes than primary tumors. Silencing YWHAG diminishes primary tumor volumes, prevents metastasis, and prolongs the median survival period of the mice.

Barriers to appropriate prescribing in older adults with multimorbidity: A modified Delphi study.

OBJECTIVES: We aimed to understand the barriers experienced by physicians when prescribing for older adults with multimorbidity in specialist outpatient clinics in Singapore. METHODS: A modified Delphi study was conducted via email with 20 panel experts in the field of geriatric medicine. Barriers identified from an earlier scoping review were presented as statements to the panel. RESULTS: Eleven barrier statements reached consensus with high importance according to the Delphi panel. Of these statements, seven (64%) belong to the domain of Environmental context and resources in the Theoretical Domains Framework (TDF), while the remaining barriers belong to the domains of skills, knowledge, intentions, and professional/social role and identity. The barriers are further linked to intervention functions in the Behaviour Change Wheel (BCW). CONCLUSION: Linking the TDF domains to intervention functions revealed strategic directions for the development of an intervention to address the barriers and optimize prescribing.

Intervention elements to reduce inappropriate prescribing for older adults with multimorbidity receiving outpatient care: a scoping review.

OBJECTIVE: Polypharmacy occurs in approximately 30% of older adults aged 65 years or more, particularly among those with multimorbidity. With polypharmacy, there is an associated risk of potentially inappropriate prescribing (PIP). The aims of this scoping review were to (1) identify the intervention elements that have been adopted to reduce PIP in the outpatient setting and (2) determine the behaviour change wheel (BCW) intervention functions performed by each of the identified intervention elements. DESIGN: Scoping review DATA SOURCES: PubMed, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Web of Science and Cochrane Library databases, grey literature sources, six key geriatrics journals and the reference lists of review papers. STUDY SELECTION: All studies reporting an intervention or strategy that addressed PIP in the older adult population (age ≥65) with multimorbidity in the outpatient setting and in which the primary prescriber is the physician. DATA EXTRACTION: Data extracted from the included studies can be broadly categorised into (1) publication details, (2) intervention details and (3) results. This was followed by data synthesis and analysis based on the BCW framework. RESULTS: Of 8195 studies yielded, 80 studies were included in the final analysis and 14 intervention elements were identified. An average of two to three elements were adopted in each intervention. The three most frequently adopted intervention elements were medication review (70%), training (26.3%) and tool/instrument(s) (22.5%). Among medication reviews, 70% involved pharmacists. The 14 intervention elements were mapped onto five intervention functions: 'education', 'persuasion', 'training', 'environmental restructuring' and 'enablement'. CONCLUSION: PIP is a multifaceted problem that involves multiple stakeholders. As such, interventions that address PIP require multiple elements to target the behaviour of the various stakeholders. The intervention elements and their corresponding functions identified in this scoping review will serve to inform the design of complex interventions that aim to reduce PIP.