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The trafficking chaperone PDE6D (or PDEδ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl binding pocket. These inhibitors suffered from low solubility and suspected off-target effects, preventing their clinical development. Here, we developed a highly soluble, low nanomolar PDE6D inhibitor (PDE6Di), Deltaflexin3, which has the lowest off-target activity as compared to three prominent reference compounds. Deltaflexin3 reduces Ras signaling and selectively decreases the growth of KRAS mutant and PDE6D -dependent cancer cells. We further show that PKG2-mediated phosphorylation of Ser181 lowers K-Ras binding to PDE6D. Thus, Deltaflexin3 combines with the approved PKG2 activator Sildenafil to more potently inhibit PDE6D/K-Ras binding, cancer cell proliferation, and microtumor growth. As observed previously, inhibition of Ras trafficking, signaling, and cancer cell proliferation remained overall modest. Our results suggest reevaluating PDE6D as a K-Ras surrogate target in cancer.

Oral healthcare among the frail is an underestimated geriatric care element. While neglected oral health (OH) is a well-established risk factor for frailty, frailty can be a risk factor for subsequent OH problems. The cross-sectional investigation nested into the SAPALDIA sub-cohort of citizens aged 52 years and older, aims to stimulate longitudinal research into aspects that accelerate poor OH among frail individuals. The hypothesis investigated was that (pre-) frail individuals are more likely to have missing teeth replaced with removable dental prostheses (RDP) resulting in difficulties with chewing. The study included 1489 participants undergoing geriatric assessments and oral examination. The main predictor was frailty status (non-frail; pre-frail; frail), based on Fried's frailty phenotype. The main outcomes of interest were non-functional dentition (presence of ≤ 19 natural teeth), presence of any RDP and self-reported difficulties with chewing. Pre-frailty and frailty were not associated with the presence of ≤ 19 natural teeth, but were associated with a higher RDP prevalence. The presence of at least one complete denture (CD) had 1.71 fold and 2.54 folds higher odds among pre-frail and frail, respectively, compared to non-frail individuals. Frail individuals with CD reported chewing difficulties 7.8 times more often than non-frail individuals without CD. The results are in line with the hypothesis that (pre-) frail individuals may be more likely to have tooth loss restored by RDPs. Future longitudinal research needs to assess potential barriers to oral hygiene and fixed dental prostheses among (pre-) frail and to study their oral health-related quality of life., Competing Interests: The authors declare that they have no competing interests., (Copyright 2024 SWISS DENTAL JOURNAL SSO – Science and Clinical Topics. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

Objectives: This study aims to quantify the cross-sectional and prospective associations between quality of life (QoL) and moderate-to-vigorous physical activity (MVPA). Methods: This study was based on the Swiss children's Objectively measured PHYsical Activity cohort. The primary endpoint is the overall QoL score and its six dimensions. The main predictor is the average time spent in MVPA per day. Linear mixed effects and linear regression models respectively were used to investigate the cross-sectional and prospective associations between MVPA and QoL. Results: There were 352 participants in the study with complete data from baseline (2013-2015) and follow-up (2019). MVPA was positively associated with overall QoL and physical wellbeing ( p = 0.023 and 0.002 respectively). The between-subject MVPA was positively associated with the overall QoL, physical wellbeing, and social wellbeing ( p = 0.030, 0.017, and 0.028 respectively). Within-subject MVPA was positively associated with physical wellbeing and functioning at school ( p = 0.039 and 0.013 respectively). Baseline MVPA was not associated with QoL 5 years later. Conclusion: Future longitudinal studies should employ shorter follow-up times and repeat measurements to assess the PA and QoL association., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2024 Darkhawaja, Hänggi, Schaffner, Kwiatkowski, Alkaiyat, Dössegger, Kayser, Suggs, Bringolf-Isler and Probst-Hensch.)

Time reference is used to build the temporal framework of discourse and is essential in ensuring efficient communication. Several studies have reported time reference deficits in fluent and non-fluent aphasia and have shown that tenses (past, present, future) are not all impaired to the same extent. However, there is little consensus on the dissociations between tenses, and the question of the influence of the type of aphasia (fluent vs. non-fluent) on time reference remains open. Therefore, a systematic review and an individual participant data meta-analysis (or mega-analysis) were conducted to determine (1) whether one tense is more impaired than another in fluent and non-fluent aphasia and, if so, (2) which task and speaker-related factors moderate tense effects. The systematic review resulted in 35 studies reporting the performance in time reference of 392 participants. The mega-analysis was then performed on 23 studies for a total of 232 participants and showed an alteration of past tense compared to present and future tenses in both types of aphasia. The analysis also showed a task and an age effect on time reference but no gender effect, independently of tenses. These results add to our knowledge of time reference in aphasia and have implications for future therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cordonier, Schaffner, Zeroual and Fossard.)