SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1.

PTOV1 is an oncogenic protein, initially identified in prostate cancer, that promotes proliferation, cell motility, and invasiveness. However, the mechanisms that regulate PTOV1 remain unclear. Here, we identify 14-3-3 as a PTOV1 interactor and show that high levels of 14-3-3 expression, like PTOV1, correlate with prostate cancer progression. We discover an SGK2-mediated phosphorylation of PTOV1 at S36, which is required for 14-3-3 binding. Disruption of the PTOV1-14-3-3 interaction results in an accumulation of PTOV1 in the nucleus and a proteasome-dependent reduction in PTOV1 protein levels. We find that loss of 14-3-3 binding leads to an increase in PTOV1 binding to the E3 ubiquitin ligase HUWE1, which promotes proteasomal degradation of PTOV1. Conversely, our data suggest that 14-3-3 stabilizes PTOV1 protein by sequestering PTOV1 in the cytosol and inhibiting its interaction with HUWE1. Finally, our data suggest that stabilization of the 14-3-3-bound form of PTOV1 promotes PTOV1-mediated expression of cJun, which drives cell-cycle progression in cancer. Together, these data provide a mechanism to understand the regulation of the oncoprotein PTOV1. IMPLICATIONS: These findings identify a potentially targetable mechanism that regulates the oncoprotein PTOV1.

Proportion of Severe Asthma Patients Eligible for Mepolizumab Therapy by Age and Age of Onset of Asthma.

BACKGROUND: Mepolizumab is an anti-IL-5 antibody approved for the treatment of severe eosinophilic asthma. However, the prevalence of patients with severe asthma eligible for mepolizumab remains unknown, especially among children. OBJECTIVE: To determine, in a population of patients with severe asthma from a tertiary referral center, the proportion of patients with an eosinophilic phenotype who would be eligible for mepolizumab, when stratified for the age of onset of asthma, and the prevalence of phenotypic features that favor mepolizumab therapy. METHODS: An extensive database of 245 adults and children referred for severe asthma was used. The prevalence of severe asthma was estimated by using the European Respiratory Society/American Thoracic Society criteria. Patients with an eosinophilic uncontrolled phenotype qualified for mepolizumab. RESULTS: In our cohort, 216 (88%) had severe asthma. Based on blood eosinophils of either greater than or equal to 150 cells/µL or greater than or equal to 300 cells/µL, 61%/41% had an eosinophilic phenotype, while 49%/34% were eligible for mepolizumab therapy. A greater percentage of adults (60%/47% of adults with asthma onset in adulthood [AoA] and 48%/26% adults with childhood-onset asthma [<18 years, CoA]) were eligible compared with children (33%/24%), for eosinophil counts of ≥150 and ≥300 cells/µL, respectively; P < .05. Compared with adults, children had a similar number of exacerbations while having better lung function (P < .05). Among adults, those with AoA were older, were more likely to have nasal polyps (28% vs 5%; P < .05), and had higher blood eosinophil counts (272 vs 150 cells/µL; P < .05) compared with those with CoA, with no difference in lung function noted between the 2 groups. Subjects showing greater than or equal to 500 eosinophils/µL, a strong indicator for mepolizumab therapy, had more nasal polyps, higher inhaled steroid dose, lower lung function, and AoA predominance than did those with less than 500 eosinophils/µL (P < .05). CONCLUSIONS: A smaller percentage of children with severe asthma were eligible for mepolizumab compared with their adult peers. Severe AoA has distinct phenotypic features that favor treatment with mepolizumab, including greater eosinophilia and nasal polyposis, in contrast to CoA, which appears to have fewer features of type 2 mucosal inflammation.

"Getting the lead out" in Hartford, Connecticut: a multifaceted lead-poisoning awareness campaign.

As part of a citywide effort to increase lead poisoning awareness within the city of Hartford, Connecticut, the Hartford Health Department implemented a multifaceted public health campaign involving several novel elements and partnerships, including the use of municipal sanitation trucks to disseminate lead-poisoning prevention messages throughout the city. To evaluate campaign reach and effectiveness, Health Department personnel collected measures of lead-poisoning knowledge, recall of campaign components, and reports of steps taken to prevent lead poisoning from 180 largely ethnic minority parents of preschool-age children. Key results were as follows: a) Recall of campaign components ranged from 21.5 to 62.6%, with newspaper advertisements and signs on buses and billboards recalled most often and a video broadcast on public-access television recalled least often. b) More than 45% of respondents reported that they took steps to prevent lead poisoning because of at least one of the campaign components, with the newspaper advertisements being the most effective component in terms of prompting lead-poisoning prevention behavior. c) Respondents' awareness was particularly low in terms of how medical personnel and procedures can and cannot detect and prevent lead poisoning in children. This campaign prompted caregivers to take steps to prevent lead poisoning and may help public health professionals in other communities to develop novel ideas through which to embark on similar initiatives.