Integrated analysis of single-cell chromatin state and transcriptome identified common vulnerability despite glioblastoma heterogeneity.

In 2021, the World Health Organization reclassified glioblastoma, the most common form of adult brain cancer, into isocitrate dehydrogenase (IDH)-wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intratumoral heterogeneity is a key contributor to therapeutic failure. To better define this heterogeneity, genome-wide chromatin accessibility and transcription profiles of clinical samples of glioblastomas and G4 IDHm astrocytomas were analyzed at single-cell resolution. These profiles afforded resolution of intratumoral genetic heterogeneity, including delineation of cell-to-cell variations in distinct cell states, focal gene amplifications, as well as extrachromosomal circular DNAs. Despite differences in IDH mutation status and significant intratumoral heterogeneity, the profiled tumor cells shared a common chromatin structure defined by open regions enriched for nuclear factor 1 transcription factors (NFIA and NFIB). Silencing of NFIA or NFIB suppressed in vitro and in vivo growths of patient-derived glioblastomas and G4 IDHm astrocytoma models. These findings suggest that despite distinct genotypes and cell states, glioblastoma/G4 astrocytoma cells share dependency on core transcriptional programs, yielding an attractive platform for addressing therapeutic challenges associated with intratumoral heterogeneity.

Prevalence of Elevated ALT in Adolescents in the US 2011-2018.

OBJECTIVE: The objective of this study is to characterize suspected nonalcoholic fatty liver disease (NAFLD) using elevated alanine aminotransferase (ALT) in a diverse and nationally representative cohort of adolescents and to characterize higher ALT elevation in adolescents with obesity. METHODS: Data from the National Health and Nutrition Examination Survey 2011-2018 were analyzed for adolescents 12-19 years. Participants with causes for elevated ALT other than NAFLD were excluded. Race and ethnicity, sex, body mass index (BMI), and ALT were examined. Elevated ALT was defined as >22 U/L (females) and >26 U/L (males) using the biologic upper normal limit (ULN). Elevated ALT thresholds up to 2X-ULN were examined among adolescents with obesity. Multivariable logistic regression was used to determine the association of race/ethnicity and elevated ALT, adjusting for age, sex, and BMI. RESULTS: Prevalence of elevated ALT in adolescents was 16.5% overall and 39.5% among those with obesity. For White, Hispanic, and Asian adolescents, prevalence was 15.8%, 21.8%, and 16.5% overall, 12.8%, 17.7%, and 27.0% in those with overweight, and 43.0%, 43.5%, and 43.1% in those with obesity, respectively. Prevalence was much lower in Black adolescents (10.7% overall, 8.4% for overweight, 20.7% for obesity). Prevalence of ALT at 2X-ULN was 6.6% in adolescents with obesity. Hispanic ethnicity, age, male sex, and higher BMI were independent predictors of elevated ALT. CONCLUSIONS: Prevalence of elevated ALT in U.S. adolescents is high, affecting 1 in 6 adolescents during 2011-2018. The risk is highest in Hispanic adolescents. Asian adolescents with elevated BMI may comprise an emerging risk group for elevated ALT.

Association of Subjective and Objective Measures of Sleep With Gut Microbiota Composition and Diversity in Older Men: The Osteoporotic Fractures in Men Study.

BACKGROUND: Growing evidence suggests bidirectional links between gut microbiota and sleep quality as shared contributors to health. Little is known about the relationship between microbiota and sleep among older persons. METHODS: We used 16S rRNA sequencing to characterize stool microbiota among men (n = 606, mean [standard deviation] age = 83.9 [3.8]) enrolled in the Osteoporotic Fractures in Men (MrOS) study from 2014 to 2016. Sleep was assessed concurrently by a questionnaire (Pittsburgh Sleep Quality index [PSQI]), and activity monitor to examine timing (acrophase) and regularity of patterns (F-statistic). Alpha diversity was measured using Faith's phylogenetic diversity (PD). Beta diversity was calculated with robust Aitchison distance with matrix completion (RPCA) and phylogenetic-RPCA (PRPCA). Their association with sleep variables was tested with partial distance-based redundancy analysis (dbRDA). Predictive-ratio biomarkers associated with sleep measurements were identified with CoDaCoRe. RESULTS: In unadjusted analyses, men with poor sleep (PSQI >5) tended to have lower alpha diversity compared to men with normal sleep (Faith's PD, beta = -0.15; 95% confidence interval [CI]: -0.30 to 0.01, p = .06). Sleep regularity was significantly associated with RPCA and PRPCA, even after adjusting for site, batch, age, ethnicity, body mass index, diabetes, antidepressant and sleep medication use, and health behaviors (RPCA/PRPCA dbRDA; p = .033/.002). In taxonomic analysis, ratios of 7:6 bacteria for better regularity (p = .0004) and 4:7 for worse self-reported sleep (p = .005) were differentially abundant: some butyrate-producing bacteria were associated with better sleep characteristics. CONCLUSIONS: Subjective and objective indicators of sleep quality suggest that older men with better sleep patterns are more likely to harbor butyrate-producing bacteria associated with better health.

Resting State Abnormalities of the Default Mode Network in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

BACKGROUND: Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach. OBJECTIVE: We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups. METHODS: PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences. RESULTS: Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies. CONCLUSIONS: The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.