The brain-derived neurotrophic factor (BDNF) gene plays an important role in modulating the stress-response axis and inflammation, which can be regulated by epigenetic mechanisms. BNDF methylation has been associated with stress-related psychiatric disorders such as depression, anxiety and post-traumatic stress. Previous studies have reported that stressful events are involved with long-lasting alterations in DNA methylation (DNAm) of the BNDF exon IV promoter, suggesting that glucocorticoids and inflammatory cytokines can regulate this process. We previously found that perceived psychological stress is modulated by inflammatory cytokines, such as interleukin (IL)-6, IL-8 and IL-10, and IL-12p70, suggesting their role in mediating the stress response. However, the epigenetic mechanism mediating this response has yet to be fully understood. In this study, we propose that high perceived stress and high serum levels of inflammatory cytokines may correlate with specific methylation sites within the BNDF exon IV promoter. To address these questions, we conducted a cross-sectional study of 82 adult women teachers working in basic education in Brazil. The perceived stress scale was used to assess stress and blood samples were collected for the measurement of inflammatory markers and BNDF methylation through flow cytometry assay and DNA pyrosequencing, respectively. We detected differentially methylated CpG sites in the BNDF gene, where 5 CpG sites were directly correlated with high stress levels. However, 4 CpG sites showed inverse effects, indicating that changes in methylation levels in those sites could lead to a protective effect on perceived stress. About inflammatory markers, IL-6 and IL-8 were associated with high perceived stress. However, only IL-8 and IL-10 showed simultaneous modulation of perceived stress, while IL-10 and IL12p70 correlated with DNAm. We found that higher levels in IL-10 and IL-12p70 serum decrease methylation in CpG11. A direct relationship was also found to IL-12p70, where higher levels in serum increase methylation in CpG5 and 13, respectively. Taken as a whole, our findings reinforce the hypothesis regarding stress-sensitive regions within the BDNF gene, mainly for CpG5, 11, and 13. In addition to these results, CpG7 and 9 may be regarded as stress-protective regions. Our data suggest that BDNF DNAm in the blood may represent a novel biomarker for early detection of adverse effects of chronic exposure to stress in healthy individuals.

To examine the effect of a mindfulness-based program specifically designed for teachers in reducing perceived stress and improving the quality of experienced emotion in female active working teachers. A second outcome evaluated is the associated change in cellular inflammatory activity, measured by peripheral blood levels of cytokines. Eighty-eight female active teachers from public schools from São Paulo Municipality were recruited, and randomly allocated to an eight-week Mindfulness-Based Health Program for Educators (MBHP-Educa) or to Neuroscience for Education Program (Neuro-Educa: active control group). The venue of both programs were several public school facilities, where many of the teachers actually worked. Both groups received activities during eight weeks in a 2 ​h/week regimen, totalizing 16 ​h. Sixty-five participants completed the program and pre- and post-interventions measures were taken from the following scales: Interpersonal Multidimensional Reactivity Scale (IRI), Positive-and-Negative Affects Scale (PANAS), Perceived Stress Scale (PSS), Connor-Davidson Resilience Scale (CD-RISC), and a primary outcome in Ryff's Psychological Well-Being Scale (PBWS). At pre-and post-intervention, blood samples were collected for the measurement of several important inflammatory biomarkers, Tumor Necrosis Factor – α (TNF-α), Interleukin 1β (IL-1β), Interleukin 6 (IL-6), Interleukin 8 (IL-8), Interleukin 10 (IL-10) and Interleukin 12p70 (IL-12P70) through flow cytometry assay. Intervention effects were analyzed via Generalized mixed models (GLMM). According to the GLMM, MBHP-Educa significantly reduced the scores of perceived stress (p ​< ​0.0001), and negative affect (p ​< ​0.0001) compared to active control group (Neuro-Educa). Conversely, an increase was observed on Psychological Well Being Scale in dimensions of Self-acceptance (p ​< ​0.0001), and Autonomy (p ​= ​0.001), as well as improvements in Resilience (p ​< ​0.0001), and Positive Affect (p ​< ​0.0001). MBHP-Educa also promoted a reduction in the levels of IL-6 (p ​= ​0.003), IL-8 (p ​= ​0.036), and increase in the levels of IL-10 (p ​< ​0.0001) and IL-12p70 (p ​< ​0.044). TNF-α, IL-1β, and IL-10p70 showed results below theoretical limit of detection accepted for CBA kit. Our data suggest that mindfulness-based interventions introduced as a strategy for reducing stress, promoting well-being and improve immune function can be a useful asset in promoting psychological health among teachers in Basic Education.

Dishevelled (DVL) is a crucial component of the Wnt-signaling pathway and is vital for multiple physiological processes. Previously thought to have a classically cytoplasmic role, the discovery of DVL nuclear translocation reframed how it is viewed functionally. Although significant progress has been made in understanding the nuclear functions of DVL, further research is required to clarify its roles in transcriptional and epigenetic regulation. A key unresolved question is whether nuclear DVL1 associates with a transcription factor partner. We show here that modulation of DVL1 expression globally affects the transcriptomic landscape. Additionally, analysis of DVL1 ChIP-sequencing allowed us to map genome-wide binding sites, revealing the extensive reach of DVL1 binding. Integration of RNA-sequencing and ChIP-sequencing further revealed ETS1 as a transcription factor binding partner which targets nuclear DVL1 to specific genomic loci. These findings provide insight into the contribution of DVL1 in transcription and clarify aspects of its elusive nuclear function.

Background: Breast cancer is a complex and heterogeneous disease characterized by distinct molecular subtypes with varying prognoses and treatment responses. Multiple factors influence breast cancer outcomes including tumor biology, patient characteristics, and treatment modalities. Demographic factors such as age, race/ethnicity, menopausal status, and body mass index have been correlated with variations in incidence, mortality, and survival rates. Over the past decade, comprehensive genomic profiling has been widely used to identify molecular biomarkers and signatures to develop novel therapeutic strategies for patients. For instance, the FLEX registry (NCT03053193) enrolled stage I–III breast cancer patients across 90 institutions in the United States and stratified risk groups based on a 70-gene signature (MammaPrint^®-MP) and molecular subtype based on an 80-gene signature (BluePrint^®-BP). This study aimed to identify the gene expression patterns and biomarkers associated with breast cancer risk and progression by integrating transcriptomic and clinical data. Methods: Targeted 111 unique gene expression and clinical data points from 978 breast cancer samples, representing each BP subtype (26% Luminal A, 26% Luminal B, 25% Basal, 23% HER2), obtained from Agendia Inc. These genes were selected based on their involvement in the mercapturic acid pathway, white and brown adipose tissue markers, inflammation markers, tumor-associated genes, apoptosis, autophagy, and ER stress markers. All statistical analyses, including principal component analysis (PCA), were performed using R version [4.4.0]. Prognostic values and genetic alterations were investigated using various web-based programs as described in the Methods section. Results: PCA of gene expression data revealed distinct clustering patterns associated with risk categories and molecular subtypes, particularly with principal component 4 (PC4). Genes related to oxidative stress, autophagy, apoptosis, and histone modification showed altered expression across risk categories and molecular subtypes. Key differentially expressed genes included SOD2, KLK5, KLK7, IL8, GSTM1/2, GLI1, CBS, and IGF1. Pathway analysis highlighted the enrichment of processes related to autophagy, cellular stress response, apoptosis, glutathione metabolism, deacetylation, and oxidative stress in high-risk and basal-like tumors compared with Ultralow and Luminal A tumors, respectively. Conclusions: This study identified gene expression signatures associated with breast cancer risk and molecular subtypes. These findings provide insights into the biological processes that may drive breast cancer progression and could inform the development of prognostic biomarkers and personalized therapeutic strategies.

Purpose: Cryoablation eradicates tumors through repeated freeze–thaw cycles and preserves tumor-associated antigens, triggering inflammatory signals capable of priming anti-tumor immunity, yet its therapeutic potential in triple-negative breast cancer (TNBC) remains largely unexplored. Immune checkpoint inhibitors (ICIs) have shown clinical benefit in TNBC but come with significant immune-related toxicities. Combining cryoablation with ICIs in TNBC may amplify the efficacy of cryoablation, which is significantly less toxic than ICIs, thereby providing opportunities for lowering the doses of ICIs in clinical practice. Here, we investigated the therapeutic impact of cryoablation with ICIs in an orthotopic bilateral murine TNBC model. Methods: Two weeks after tumor induction, primary tumors were cryoablated while the abscopal tumors were not manipulated and represented distant tumors. Twenty-four hours pre- and post-cryoablation, mice received an intra-peritoneal injection of PBS or ICIs (anti-CTLA-4, PD-1, or PD-L1). Tumors, tumor-draining lymph nodes (TdLNs), spleen, and peripheral blood were assessed for immune profiling a week later. Results: Preliminary analyses demonstrated that combining cryoablation with anti-CTLA-4 enhanced T cell activation systemically compared to cryoablation alone or in combination with PD-1/PD-L1 blockade. Notably, relative to cryoablation monotherapy, combination with anti-CTLA-4 increased the frequencies of activated CD4⁺ and CD8⁺ T cells in the abscopal tumors, while also inducing a higher frequency and activation of conventional dendritic cells in the abscopal TdLNs. Conclusion: These results suggest combination of cryoablation with anti-CTLA-4 therapy enhances systemic antitumor immunity by boosting antigen presentation. Our results support further investigation into this combination strategy to prevent tumor recurrence and metastasis while minimizing toxicity of treatment.