FOXO3-NF-κB RelA Protein Complexes Reduce Proinflammatory Cell Signaling and Function.

Tumor-associated myeloid cells, including dendritic cells (DCs) and macrophages, are immune suppressive. This study demonstrates a novel mechanism involving FOXO3 and NF-κB RelA that controls myeloid cell signaling and impacts their immune-suppressive nature. We find that FOXO3 binds NF-κB RelA in the cytosol, impacting both proteins by preventing FOXO3 degradation and preventing NF-κB RelA nuclear translocation. The location of protein-protein interaction was determined to be near the FOXO3 transactivation domain. In turn, NF-κB RelA activation was restored upon deletion of the same sequence in FOXO3 containing the DNA binding domain. We have identified for the first time, to our knowledge, a direct protein-protein interaction between FOXO3 and NF-κB RelA in tumor-associated DCs. These detailed biochemical interactions provide the foundation for future studies to use the FOXO3-NF-κB RelA interaction as a target to enhance tumor-associated DC function to support or enhance antitumor immunity.

Recruitment of Older Adults: Success May Be in the Details.

PURPOSE: Describe recruitment strategies used in a randomized clinical trial of a behavioral prospective memory intervention to improve medication adherence for older adults taking antihypertensive medication. RESULTS: Recruitment strategies represent 4 themes: accessing an appropriate population, communication and trust-building, providing comfort and security, and expressing gratitude. Recruitment activities resulted in 276 participants with a mean age of 76.32 years, and study enrollment included 207 women, 69 men, and 54 persons representing ethnic minorities. Recruitment success was linked to cultivating relationships with community-based organizations, face-to-face contact with potential study participants, and providing service (e.g., blood pressure checks) as an access point to eligible participants. Seventy-two percent of potential participants who completed a follow-up call and met eligibility criteria were enrolled in the study. The attrition rate was 14.34%. IMPLICATIONS: The projected increase in the number of older adults intensifies the need to study interventions that improve health outcomes. The challenge is to recruit sufficient numbers of participants who are also representative of older adults to test these interventions. Failing to recruit a sufficient and representative sample can compromise statistical power and the generalizability of study findings.

Biomarkers for cognitive aging part II: oxidative stress, cognitive assessments, and medication adherence.

The purpose of this study was to further examine potential biomarkers of cognitive aging by looking at the associations among oxidative stress, cognitive abilities, and medication adherence in a community-based sample of middle-aged and older adults (n = 42; mean age = 69 years) prescribed at least one medication for hypertension. In addition to measures described in Part I, "Biomarkers for Cognitive Aging," a 12-hr urine collection for F(2)-isoprostanes served as an indicator of oxidative stress. Participants completed a battery of cognitive assessments and 8 weeks of electronic medication monitoring for adherence to one antihypertensive agent. Oxidative stress was significantly associated with logical memory, immediate (r = -.38, p < .01) and delayed recall (r = -.42, p < .01), and recognition memory (r = -.42, p < .01) from the Wechsler Memory Scale III, number of perseveration errors (r = .26, p < .05) and categories achieved (r = -.26, p < .01) on the Wisconsin Card Sorting Test (WSCT), and medication adherence (r = -.34, p <.05). Findings indicate that a biomarker of oxidative stress, F(2)-isoprostanes corrected for vitamin E, is significantly associated with cognitive measures and a functional outcome.

Biomarkers for cognitive aging part I: telomere length, blood pressure and cognition among individuals with hypertension.

Chronological age is used as a marker for age-associated changes in cognitive function. However, there is great interindividual variability in cognitive ability among people of the same age. Physiological age rather than chronological age should be more closely associated with age-related cognitive changes because these changes are not universal and are likely dependent on several factors in addition to the number of years lived. Cognitive function is associated with successful self-management, and a biological marker that reflects physiological age and is associated with cognitive function could be used to identify risk for failure to self-manage. The purpose of this study was to investigate the association between telomere length, a known biomarker of age; blood pressure; cognitive assessments; and adherence to antihypertensive medication among community-dwelling middle-aged and older adults. The authors administered a battery of cognitive assessments to 42 participants (M = 69 years of age), collected blood samples, and isolated peripheral blood mononuclear leukocytes for genomic DNA. The authors determined relative telomere length using Cawthon's method for real-time quantitative polymerase chain reaction (RT-qPCR) and measured medication adherence using an electronic medication monitoring system (MEMS by Aardex) over 8 weeks. Findings indicate that telomere length was inversely associated with systolic blood pressure (r = -.38, p < .01) and diastolic blood pressure (r = -.42, p < .01) but not with cognitive assessments or adherence. The authors discuss the nonsignificant findings between telomere length and cognitive assessments including the potential modifying role of gender.

Genetic variation in genes associated with arsenic metabolism: glutathione S-transferase omega 1-1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans.

Individual variability in human arsenic metabolism has been reported frequently in the literature. This variability could be an underlying determinant of individual susceptibility to arsenic-induced disease in humans. Recent analysis revealing familial aggregation of arsenic metabolic profiles suggests that genetic factors could underlie interindividual variation in arsenic metabolism. We screened two genes responsible for arsenic metabolism, human purine nucleoside phosphorylase (hNP), which functions as an arsenate reductase converting arsenate to arsenite, and human glutathione S-transferase omega 1-1 (hGSTO1-1), which functions as a monomethylarsonic acid (MMA) reductase, converting MMA(V) to MMA(III), to develop a comprehensive catalog of commonly occurring genetic polymorphisms in these genes. This catalog was generated by DNA sequencing of 22 individuals of European ancestry (EA) and 24 individuals of indigenous American (IA) ancestry. In (Italic)hNP(/Italic), 48 polymorphic sites were observed, including 6 that occurred in exons, of which 1 was nonsynonymous (G51S). One intronic polymorphism occurred in a known enhancer region. In hGSTO1-1, 33 polymorphisms were observed. Six polymorphisms occurred in exons, of which 4 were nonsynonymous. In contrast to hNP, in which the IA group was more polymorphic than the EA group, in hGSTO1-1 the EA group was more polymorphic than the IA group, which had only 1 polymorphism with a frequency > 10%. Populations representing genetic admixture between the EA and IA groups, such as Mexican Hispanics, could vary in the extent of polymorphism in these genes based upon the extent of admixture. These data provide a framework in which to conduct genetic association studies of these two genes in relevant populations, thereby allowing hNP and hGSTO1-1 to be evaluated as potential susceptibility genes in human arsenicism.