FOXOs support the metabolic requirements of normal and tumor cells by promoting IDH1 expression.

FOXO transcription factors are considered bona fide tumor suppressors; however, recent studies showed FOXOs are also required for tumor survival. Here, we identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. In cancer cells carrying mutant IDH1, FOXOs likewise stimulate mutant IDH1 expression and maintain the levels of the oncometabolite 2-hydroxyglutarate, which stimulates cancer cell proliferation and inhibits TET enzymes and histone demethylases. Combined, our data provide a new paradigm for the paradoxical role of FOXOs in both tumor suppression and promotion.

Psychometric properties of the Greek version of Jacelon Attributed Dignity Scale.

BACKGROUND: Maintaining dignity is important for successful aging, but there is lack of validated research instruments in the nursing literature to investigate dignity as perceived by the old people. OBJECTIVE: This is a methodological study aiming to investigate the psychometric properties of the Greek version of Jacelon Attributed Dignity Scale as translated in the Greek language. RESEARCH DESIGN: A methodological approach consisting of translation, adaptation, and cross-cultural validation. A sample of 188 Greek-speaking old Cypriot persons drawn from the Hospital outpatient departments was asked to complete the Greek versions of Jacelon Attributed Dignity Scale and the Instrumental Activities of Daily Living. Data analyses included internal consistency reliability (Cronbach's alpha coefficient), item analysis, and exploratory factor analysis using principal component method with orthogonal varimax rotation. Ethical considerations: The study protocol was approved by the National Bioethics committee according to the national legislation. Permission to use the research instrument was granted from the author. Information about the aim and the benefits of the study was included in the information letter. FINDINGS: Cronbach's alpha for Greek version of Jacelon Attributed Dignity Scale was 0.90. Four factors emerged explaining 65.28% of the total variance, and item to total correlation values ranged from 0.25 to 0.74 indicating high internal consistency and homogeneity. Mean item score in Instrumental Activities of Daily Living was 5.6 (standard deviation = 1.7) for men and 6.7 (standard deviation = 1.7) for women, and the correlations between demographics, Instrumental Activities of Daily Living, and the four factors of the Greek version of Jacelon Attributed Dignity Scale were low; also in multiple linear regression, the values of R2 are presented low. DISCUSSION: Demographic characteristics and degree of functionality seem to be associated with some of the dimensions of dignity but with low correlations; therefore, they cannot predict attributed dignity. CONCLUSION: The Greek version of Jacelon Attributed Dignity Scale is a valid and reliable tool to measure attributed dignity in Greek-speaking older adults, but further testing of the psychometric properties and other potential factors that may affect the attributed dignity is needed.

Forkhead box(O) in control of reactive oxygen species and genomic stability to ensure healthy lifespan.

SIGNIFICANCE: Transcription factors of the Forkhead box O class (FOXOs) are associated with lifespan and play a role in age-related diseases. FOXOs, therefore, serve as a paradigm for developing an understanding as to how age-related diseases, such as cancer and diabetes interconnect with lifespan. Understanding the regulatory inputs on FOXO may reveal how changes in these regulatory signaling pathways affect disease and lifespan. RECENT ADVANCES: Numerous regulators of FOXO have now been described and a clear and evolutionary conserved role has emerged for phosphoinositide-3 kinase/protein kinase B (also known as c-Akt or AKT) signaling and c-jun N-terminal kinase signaling. Analysis of FOXO function in the context of these signaling pathways has shown the importance of FOXO-mediated transcriptional regulation on cell cycle progression and other cell fates, such as cell metabolism, stress resistance, and apoptosis in mediating disease and lifespan. CRITICAL ISSUES: Persistent DNA damage is also tightly linked to disease and aging; yet, data on a possible link between DNA damage and FOXO have been limited. Here, we discuss possible connections between FOXO and the DNA damage response in the context of the broader role of connecting lifespan and disease. FUTURE DIRECTIONS: Understanding the role of lifespan in diseases onset may provide unique and generic possibilities to intervene in disease processes to ensure a healthy lifespan.

The primary folding defect and rescue of ΔF508 CFTR emerge during translation of the mutant domain.

In the vast majority of cystic fibrosis (CF) patients, deletion of residue F508 from CFTR is the cause of disease. F508 resides in the first nucleotide binding domain (NBD1) and its absence leads to CFTR misfolding and degradation. We show here that the primary folding defect arises during synthesis, as soon as NBD1 is translated. Introduction of either the I539T or G550E suppressor mutation in NBD1 partially rescues ΔF508 CFTR to the cell surface, but only I539T repaired ΔF508 NBD1. We demonstrated rescue of folding and stability of NBD1 from full-length ΔF508 CFTR expressed in cells to isolated purified domain. The co-translational rescue of ΔF508 NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis.