Objectives: The objectives of this study were to evaluate whether a mindfulness meditation intervention may be effective in caregivers of close relatives with dementia and to help refine the protocol for future larger trials. Design: The design was a pilot randomized trial to evaluate the effectiveness of a mindfulness meditation intervention adapted from the Mindfulness-Based Cognitive Therapy program in relation to two comparison groups: an education class based on Powerful Tools for Caregivers serving as an active control group and a respite-only group serving as a pragmatic control. Settings/location: This study was conducted at the Oregon Health & Science University, Portland, OR. Subjects: The subjects were community-dwelling caregivers aged 45-85 years of close relatives with dementia. Interventions: The two active interventions lasted 7 weeks, and consisted of one 90-minute session per week along with at-home implementation of knowledge learned. The respite-only condition provided the same duration of respite care that was needed for the active interventions. Outcome measures: Subjects were assessed prior to randomization and again after completing classes at 8 weeks. The primary outcome measure was a self-rated measure of caregiver stress, the Revised Memory and Behavior Problems Checklist (RMBPC). Secondary outcome measures included mood, fatigue, self-efficacy, mindfulness, salivary cortisols, cytokines, and cognitive function. We also evaluated self-rated stress in the subjects' own environment, expectancy of improvement, and credibility of the interventions. Results: There were 31 caregivers randomized and 28 completers. There was a significant effect on RMBPC by group covarying for baseline RMBPC, with both active interventions showing improvement compared with the respite-only group. Most of the secondary outcome measures were not significantly affected by the interventions. There was an intervention effect on the caregiver self-efficacy measure and on cognitive measures. Although mindfulness was not impacted by the intervention, there were significant correlations between mindfulness and self-rated mood and stress scores. Conclusions: Both mindfulness and education interventions decreased the self-rated caregiver stress compared to the respite-only control.

TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.

Findings from previous research assessing sleep quality in caregivers are inconsistent due to differences in sleep assessment methods. This study evaluated sleep in dementia caregivers using a comprehensive sleep assessment utilizing an ambulatory polysomnography (PSG) device. Twenty caregivers and twenty non-caregivers rated their perceived sleep quality, stress, and depressive symptoms; provided samples of cortisol and inflammatory biomarkers; and completed an objective sleep assessment using a portable PSG device. Caregivers reported greater perceived stress than non-caregivers. Next, the groups had different sleep architecture: caregivers spent less proportion of their sleep in restorative sleep stages compared to non-caregivers. Further, levels of C-reactive protein and awakening salivary cortisol were greater in caregivers than in non-caregivers, and these measures were related to sleep quality. Our findings indicate that sleep disruption is a significant concomitant of caregiving and may affect caregiver’s health. Sleep quality of caregivers might be a useful target for a clinical intervention.

SUMMARY Environmental cues provoke rapid transitions in gene expression to support growth and cellular plasticity through incompletely understood mechanisms. Lin28 RNA-binding proteins have evolutionarily conserved roles in post-transcriptional coordination of pro-growth gene expression, but signaling pathways allowing trophic stimuli to induce Lin28 have remained uncharacterized. We find that Lin28a protein exhibits rapid basal turnover in neurons and that mitogen-activated protein kinase (MAPK)-dependent phosphorylation of the RNA-silencing factor HIV TAR-RNA-binding protein (TRBP) promotes binding and stabilization of Lin28a, but not Lin28b, with an accompanying reduction in Lin28-regulated miRNAs, downstream of brain-derived neurotrophic factor (BDNF). Binding of Lin28a to TRBP in vitro is also enhanced by phospho-mimic TRBP. Further, phospho-TRBP recapitulates BDNF-induced neuronal dendritic spine growth in a Lin28a-dependent manner. Finally, we demonstrate MAPK-dependent TRBP and Lin28a induction, with physiological function in growth and survival, downstream of diverse growth factors in multiple primary cell types, supporting a broad role for this pathway in trophic responses.

Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase (TERT) promoter. TERT promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with TERT reactivation and telomere maintenance. Here, we demonstrate increased binding of a specific GABPB1L-isoform–containing complex to the mutant TERT promoter. Furthermore, we find that TERT promoter mutant GBM cells, unlike wild-type cells, exhibit a critical near-term dependence on GABPB1L for proliferation, notably also posttumor establishment in vivo. Up-regulation of the protein paralogue GABPB2, which is normally expressed at very low levels, can rescue this dependence. More importantly, when combined with frontline temozolomide (TMZ) chemotherapy, inducible GABPB1L knockdown and the associated TERT reduction led to an impaired DNA damage response that resulted in profoundly reduced growth of intracranial GBM tumors. Together, these findings provide insights into the mechanism of cancer-specific TERT regulation, uncover rapid effects of GABPB1L-mediated TERT suppression in GBM maintenance, and establish GABPB1L inhibition in combination with chemotherapy as a therapeutic strategy for TERT promoter mutant GBM.

Background Clinicians and researchers working with dementia caregivers typically assess caregiver stress in a clinic or research center, but caregivers’ stress is rooted at home where they provide care. The study aimed to compare ratings of stress-related measures obtained in research setting and home using ecological momentary assessment (EMA). Methods EMA of 18 caregivers (mean age 66.4±7.8, 89% females) and 23 non-caregivers (mean age 66.4±7.9, 87% females) was implemented using a personal digital assistant. Subjects rated their perceived stress, fatigue, coping with current situation, mindfulness, and situational demand once in the research center and again at 3–4 semi-random points during a day at home. The data from several assessments conducted at home were averaged for statistical analyses and compared to the data collected in the research center. Results Testing environment had a differential effect on caregivers and non-caregivers for the ratings of perceived stress (p < 0.01) and situational demand (p = 0.01). When tested in research center, ratings for all measures were similar between groups, but when tested at home, caregivers rated their perceived stress higher than non-caregivers (p = 0.02). Overall, caregivers reported higher perceived stress at home than in the research center (p = 0.02), and non-caregivers reported greater situational demand in the research center than at home (p < 0.01). Conclusions The assessment method and environment affect stress-related outcomes. Evaluating participants in their natural environment provides a more sensitive measure of stress-related outcomes. EMA provides a convenient way to gather data when evaluating dementia caregivers.

Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase (TERT) promoter. TERT promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose expression is associated with TERT reactivation and telomere maintenance. Here, using biochemical and cell biology approaches, we show direct evidence that a specific GABP complex containing the subunit protein GABPB1L forms predominantly at the mutant TERT promoter, leading to TERT re-expression. Furthermore, we find that TERT promoter mutant GBM cells, unlike wild-type cells, are immediately dependent on GABPB1L for proliferation in cell culture and post-tumor establishment in vivo. Notably, when combined with frontline temozolomide (TMZ) chemotherapy, GABPB1L knockdown and the associated TERT reduction lead to an impaired DNA damage response that results in profoundly reduced growth of intracranial GBM tumors.Together, these findings provide new insights into the mechanism of cancer-specific TERT regulation, uncover rapid effects of TERT suppression in GBM maintenance, and establish GABPB1L inhibition, alone or in combination with chemotherapy, as a therapeutic strategy for TERTp mutant GBM.

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