Integration of Kinase and Calcium Signaling at the Level of Chromatin Underlies Inducible Gene Activation in T Cells.

TCR signaling pathways cooperate to activate the inducible transcription factors NF-κB, NFAT, and AP-1. In this study, using the calcium ionophore ionomycin and/or PMA on Jurkat T cells, we show that the gene expression program associated with activation of TCR signaling is closely related to specific chromatin landscapes. We find that calcium and kinase signaling cooperate to induce chromatin remodeling at ∼2100 chromatin regions, which demonstrate enriched binding motifs for inducible factors and correlate with target gene expression. We found that these regions typically function as inducible enhancers. Many of these elements contain composite NFAT/AP-1 sites, which typically support cooperative binding, thus further reinforcing the need for cooperation between calcium and kinase signaling in the activation of genes in T cells. In contrast, treatment with PMA or ionomycin alone induces chromatin remodeling at far fewer regions (∼600 and ∼350, respectively), which mostly represent a subset of those induced by costimulation. This suggests that the integration of TCR signaling largely occurs at the level of chromatin, which we propose plays a crucial role in regulating T cell activation.

Peri-operative Outcomes and Survival Following Palliative Gastrectomy for Gastric Cancer: a Systematic Review and Meta-analysis.

BACKGROUND: Many patients with gastric cancer present with late stage disease. Palliative gastrectomy remains a contentious intervention aiming to debulk tumour and prevent or treat complications such as gastric outlet obstruction, perforation and bleeding. METHODS: We conducted a systematic review of the literature for all papers describing palliative resections for gastric cancer and reporting peri-operative or survival outcomes. Data from peri-operative and survival outcomes were meta-analysed using random effects modelling. Survival data from patients undergoing palliative resections, non-resective surgery and palliative chemotherapy were also combined. This study was registered with the PROSPERO database (CRD42019159136). RESULTS: One hundred and twenty-eight papers which included 58,675 patients contributed data. At 1 year, there was a significantly improved survival in patients who underwent palliative gastrectomy when compared to non-resectional surgery and no treatment. At 2 years following treatment, palliative gastrectomy was associated with significantly improved survival compared to chemotherapy only; however, there was no significant improvement in survival compared to patients who underwent non-resectional surgery after 1 year. Palliative resections were associated with higher rates of overall complications versus non-resectional surgery (OR 2.14; 95% CI, 1.34, 3.46; p < 0.001). However, palliative resections were associated with similar peri-operative mortality rates to non-resectional surgery. CONCLUSION: Palliative gastrectomy is associated with a small improvement in survival at 1 year when compared to non-resectional surgery and chemotherapy. However, at 2 and 3 years following treatment, survival benefits are less clear. Any survival benefits come at the expense of increased major and overall complications.