LincRNA-p21 Activates p21 In cis to Promote Polycomb Target Gene Expression and to Enforce the G1/S Checkpoint

The p53-regulated long noncoding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function, we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a coactivator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted coactivator for p53-mediated p21 expression.National Institutes of Health (U.S.)Howard Hughes Medical InstituteLudwig Center for Molecular OncologyDamon Runyon Cancer Research Foundatio

Lipid tethering of breast tumor cells enables real-time imaging of free-floating cell dynamics and drug response

Funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.Free-floating tumor cells located in the blood of cancer patients, known as circulating tumor cells (CTCs), have become key targets for studying metastasis. However, effective strategies to study the free-floating behavior of tumor cells in vitro have been a major barrier limiting the understanding of the functional properties of CTCs. Upon extracellular-matrix (ECM) detachment, breast tumor cells form tubulin-based protrusions known as microtentacles (McTNs) that play a role in the aggregation and re-attachment of tumor cells to increase their metastatic efficiency. In this study, we have designed a strategy to spatially immobilize ECM-detached tumor cells while maintaining their free-floating character. We use polyelectrolyte multilayers deposited on microfluidic substrates to prevent tumor cell adhesion and the addition of lipid moieties to tether tumor cells to these surfaces through interactions with the cell membranes. This coating remains optically clear, allowing capture of high-resolution images and videos of McTNs on viable free-floating cells. In addition, we show that tethering allows for the real-time analysis of McTN dynamics on individual tumor cells and in response to tubulin-targeting drugs. The ability to image detached tumor cells can vastly enhance our understanding of CTCs under conditions that better recapitulate the microenvironments they encounter during metastasis

Sex Differences in Physical Activity Among Individuals with Type 2 Diabetes Across the Lifespan: A Systematic Review and Meta-Analysis

   Background: Physical activity (PA) is a cornerstone of type 2 diabetes mellitus (T2DM) treatment. Sex differences in PA behavior or barriers/facilitators to PA among individuals with T2DM are unclear. Purpose: To summarize the evidence related to sex differences in participation in PA and barriers/facilitators to PA among individuals with T2DM across the lifespan. Data Source: Systematic searches (CRD42021254246) were conducted using Ovid Medline, EMBASE, Web of Science, CINAHL, AMED, PsychINFO, and SPORTDiscus. Study Selection: Studies assessing PA, sedentary behaviors (SB) or barriers/facilitators to PA among individuals with T2DM by sex or gender. Data Extraction: Participant characteristics, meeting PA guidelines, participation in PA and SB, and barriers/facilitators to PA were extracted by two independent reviewers.  Data Synthesis: Fifty-three articles (65,344 participants) were included in the systematic review; 21 articles in the meta-analysis. Sex differences were not observed in meeting PA guidelines among adolescents (OR [95% CI], 0.70 [0.31, 1.59]), but males were more likely than females to meet PA guidelines among adults (1.65 [1.36, 2.01]) and older adults (1.63 [1.27, 2.09]). Males performed more moderate to vigorous PA (MVPA) than females across all age groups. Common barriers were lack of time (men) and lack of social support and motivation (women).  Limitations: Limitations include heterogeneity of measures used to assess PA and lack of stratification of data by sex. Conclusions: Sex differences in meeting PA guidelines were not observed among adolescents, but were apparent among adults and older adults with T2DM. Females consistently engaged in less MVPA than males across the lifespan.</p