Conectar
The standard treatment of oral cavity cancers (OCC) relies on surgery and postoperative radiotherapy (poRT) for advanced stages or poor factors. In more than 75% of cases, reconstructive surgery with a flap aims to restore the function lost with tumour resection. Current poRT planning and delineation guidelines omit the presence of a flap. It may be assumed that poRT with flap sparing may allow for reducing radio-induced toxicities and improving functional outcomes, without impairing local primary control. The OPTIFLAP trial assesses non-inferior locoregional control using flap sparing compared with conventional flap-agnostic radiotherapy in patients with OCC, while reducing treatment-related toxicity and improving functional outcomes.
The OPTIFLAP study is a French, multicentre, 1:1 randomised, phase III, controlled trial. It will recruit 348 patients with OCC with a flap. Recruitment is active with the first enrolment on 2 July 2025 and is planned over 48 months. The primary outcome is non-inferior 2-year locoregional control rate using flap sparing compared with flap-agnostic radiotherapy (as per standard routine practice) in completely resected OCCs undergoing poRT. Key secondary outcomes include rates of toxicities, locoregional relapse-free survival, progression-free survival, overall survival, quality of life, functional outcomes (assessed by the Performance Status Scales for Head and Neck Cancer, the MD Anderson Dysphagia Inventory (self-questionnaire) and the Phonation Handicap Index (self-questionnaire)), flap doses and outcomes between arms depending on dosimetric parameters. The trial incorporates translational ancillary studies addressing individual radiosensitivity, salivary microbiome evolution, radiomics and dosiomics of flap changes, as well as medico-economic evaluation.
The study protocol has been approved by the Medical Ethics Committee East III (January 2025; Ref 24.05832.000442) and the French Agency for Medical and Health Products Safety (December 2024; ID-RCB: 2024-A01764-43) and was validated by review boards of all participating centres. Written informed consent will be obtained from all participants. Study results will be published in international peer-reviewed scientific journals and presented at relevant scientific conferences.
Reducing sedentary behaviour (SB) in older adults is a promising strategy to promote healthy ageing. However, to develop more effective interventions, more in-depth information is needed on how existing interventions work. The present realist review aims to identify the working mechanisms and contextual preconditions to guide the development of future interventions.
A realist review was conducted following the iterative process of Pawson and Tilley and reported following the RAMESES publication standards.
Evidence was searched in four databases: EMBASE, PubMed, Web of Science and Scopus, and in the grey literature.
All study types and designs were included. Studies conducted in older adults with a mean age of 60 years or older, providing information on the context, mechanisms and/or outcomes of interventions aimed at the reduction of SB were eligible for inclusion and appraised for relevance and rigour.
All data were coded by two independent reviewers. Sections that contained relevant information to refine, refute or confirm the initial programme theory were given a code. Based on these codes, context-mechanism-outcome configurations were made, and a final programme theory was developed.
In total, 58 studies, from 61 articles, were eligible. The review revealed three important contexts for changes in SB: the (1) motivation, (2) opportunities and (3) capabilities of older adults. Depending on the context, other behaviour change techniques should be used to trigger specific mechanisms and, in turn, reduce SB. Especially, the impact of the underlying automatic processes of SB on the effectiveness of SB interventions became clear. Existing interventions primarily focus on the reflective processes guiding SB, without taking into account that SB is often an automatic response that occurs unconsciously, with little reasoning.
The effectiveness of SB interventions in older adults highly depends on the context in which the interventions occur. In particular, the context of automatic motivation should receive more attention to break the ingrained habit of SB in older adults.
by Ian C. Lock, Nathan H. Leisenring, Warren Floyd, Eric S. Xu, Lixia Luo, Yan Ma, Erin C. Mansell, Diana M. Cardona, Chang-Lung Lee, David G. Kirsch
BackgroundThe tumor suppressor p53 (Trp53), also known as p53, is the most commonly mutated gene in cancer. Canonical p53 DNA damage response pathways are well characterized and classically thought to underlie the tumor suppressive effect of p53. Challenging this dogma, mouse models have revealed that p53-driven apoptosis and cell cycle arrest are dispensable for tumor suppression. Here, we investigated the inverse context of a p53 mutation predicted to drive the expression of canonical targets but is detected in human cancer.
MethodsWe established a novel mouse model with a single base pair mutation (GAG>GAT, p53E221D) in the DNA-Binding domain that has wild-type function in screening assays, but is paradoxically found in human cancer in Li-Fraumeni syndrome. Using mouse p53E221D and the analogous human p53E224D mutants, we evaluated expression, transcriptional activation, and tumor suppression in vitro and in vivo.
ResultsExpression of human p53E224D from cDNA translated to a fully functional p53 protein. However, p53E221D/E221D RNA transcribed from the endogenous locus is mis-spliced resulting in nonsense-mediated decay. Moreover, fibroblasts derived from p53E221D/E221D mice do not express a detectable protein product. Mice homozygous for p53E221D exhibited increased tumor penetrance and decreased life expectancy compared to p53WT/WT animals.
ConclusionsMouse p53E221D and human p53E224D mutations lead to splice variation and a biologically relevant p53 loss of function in vitro and in vivo.
FreshRSS 