ABSTRACT
Microsatellite instability-high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion and cell proliferation and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses the expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.
Subject(s)
Cell Cycle Proteins , Ribosomal Proteins , Humans , Ribosomal Proteins/metabolism , Ribosomal Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Neoplasms/genetics , Neoplasms/pathology , Neoplasms/metabolism , Cell Line, Tumor , Alternative Splicing/genetics , Cell Proliferation/genetics , Animals , Exons/genetics , Mice , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , Gene Expression Regulation, Neoplastic , Piperazines/pharmacology , Imidazoles/pharmacologyABSTRACT
BACKGROUND: Reports of children's engagement in active transportation outline low participation rates in many countries despite many associated mental, physical, and social health benefits. One of the main contributors to this phenomenon is a cited lack of education and knowledge among children regarding active travel (AT), specifically road safety. To address this issue, the aim of this study was to evaluate the feasibility and effectiveness of an online road safety education intervention to promote AT among children and their parents. METHODS: Applying the Multiphase Optimization Strategy (MOST) for intervention development, implementation, and evaluation, we designed and assessed a four-module online road safety education intervention with a sample of 57 parent-child dyads using a 23 factorial design featuring both qualitative and quantitative analyses. RESULTS: Main intervention feasibility findings include positive and critical feedback on the program's content and design, and moderate participant engagement as reflected by program retention and completion rates. With respect to the preliminary intervention effectiveness on children, a significant improvement in road safety knowledge scores was observed for groups that feature the "wheeling safety and skills" module. Slight improvements in AT knowledge scores across all the intervention groups were observed, but were not of significance. Preliminary intervention effectiveness on select parental AT practices and perceptions saw significant improvements in some groups. Groups that featured the 'wheeling safety and skills' module exhibited significantly higher guided choice scores upon completion of the program than those who did not receive this component. CONCLUSION: The MOST framework allowed us to design and evaluate the feasibility and preliminary effectiveness of an online road safety education intervention. The developed intervention has demonstrated that it has the potential to improve children's road safety knowledge and some areas of parental AT practices and perceptions, to which improvements may be attributed to the inclusion of the "wheeling safety and skills" module, suggesting that the targeted focus on cycling skills is a prioritized area. AT programming and practice implications are discussed. Future research is encouraged to refine modules to better reflect the priorities of children and parents and to test these refined components among larger samples. WORD COUNT: 9,391 (excludes abstract, tables, figures, abbreviations, and references).
Subject(s)
Feasibility Studies , Parents , Safety , Humans , Pilot Projects , Child , Male , Female , Parents/education , Parents/psychology , Adult , Program Evaluation , Accidents, Traffic/prevention & control , Health Education/methods , Automobile Driving/education , AdolescentABSTRACT
Even though regular engagement in physical activity (PA) among children can support their development and encourage the adoption of healthy lifelong habits, most do not achieve their recommended guidelines. Active travel (AT), or any form of human-powered travel (e.g., walking), can be a relatively accessible, manageable, and sustainable way to promote children's PA. One common barrier to children's engagement in AT, however, is a reported lack of education and training. To support children's participation in AT, this paper presents the development of a comprehensive 4-module online road safety education intervention designed to improve children's knowledge and confidence regarding AT. Using a qualitative integrated knowledge translation (iKT) approach undertaken with community collaborators (n = 50) containing expertise in health promotion, public safety, school administration, and transportation planning, our inductive thematic analysis generated fourth themes which constituted the foundation of the intervention modules: Active Travel Knowledge: Awareness of Benefits and Participation; Pedestrian Safety and Skills: Roles, Responsibilities, and Rules; Signs and Infrastructure: Identification, Literacy, and Behaviour; Wheeling Safety and Skills: Technical Training and Personal Maneuvers. Each theme/module was then linked to an explicit learning objective and connected to complementary knowledge activities, resources, and skill development exercises. Implications for research and practice are discussed.
Subject(s)
Translational Science, Biomedical , Travel , Child , Humans , Transportation , Schools , ExerciseABSTRACT
Microsatellite instability high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion, cell proliferation, and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.