Intra-tumoral and peripheral blood TIGIT and PD-1 as immune biomarkers in nodular lymphocyte predominant Hodgkin lymphoma.

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.

Invasion by activated macrophages requires delivery of nascent membrane-type-1 matrix metalloproteinase through late endosomes/lysosomes to the cell surface.

Macrophage migration into injured or infected tissue is a key aspect in the pathophysiology of many diseases where inflammation is a driving factor. Membrane-type-1 matrix metalloproteinase (MT1-MMP) cleaves extracellular matrix components to facilitate invasion. Here we show that, unlike the constitutive MT1-MMP surface recycling seen in cancer cells, unactivated macrophages express low levels of MT1-MMP. Upon lipopolysaccharide (LPS) activation, MT1-MMP synthesis dramatically increases 10-fold at the surface by 15 hours. MT1-MMP is trafficked from the Golgi complex to the surface via late endosomes/lysosomes in a pathway regulated by the late endosome/lysosome R-SNAREs VAMP7 and VAMP8. These form two separate complexes with the surface Q-SNARE complex Stx4/SNAP23 to regulate MT1-MMP delivery to the plasma membrane. Loss of either one of these SNAREs leads to a reduction in surface MT1-MMP, gelatinase activity and reduced invasion. Thus, inhibiting MT1-MMP transport through this pathway could reduce macrophage migration and the resulting inflammation.

The Impact of Competitive Sports on Oral Health: Exploring Their Relationship with Salivary Oxidative Stress in Children.

This article explores the correlation between salivary biomarkers, such as glutathione peroxidase (GPX), total antioxidant capacity (TAC), and superoxide dismutase (SOD), and their association with oral health for children in competitive sports. Saliva has emerged as a valuable resource for evaluating physiological and pathological conditions due to its non-invasive collection method and easy storage. This study examines the potential of GPX, TAC, and SOD as salivary biomarkers for assessing the impact of competitive sports on children's oral health. It discusses the potential implications of increased oxidative stress due to intense physical activity and the role of antioxidant defense mechanisms in maintaining oral health. In total, 173 children aged between 6 and 17 were divided into three groups, 58 hockey players, 55 football players, and 60 in the control group, and examined to assess their oral hygiene and dental and periodontal health. Saliva was collected, centrifuged, and the supernatant was analyzed for the relevant biomarkers. The findings seem to suggest that salivary biomarkers, like GPX, TAC, and SOD, might serve as indicators of the physiological response to competitive sports in children, as well as indicators of oral health, especially dental cavities, and periodontal disease. Statistical analysis showed significant differences between the groups, with better values for athletes, regardless of age, sex, or activity type. Understanding the relationship between salivary biomarkers and competitive sports in children can have significant implications for monitoring and optimizing the health and performance of young athletes. Further research is needed to establish the specific associations between these biomarkers and the effects of several types and intensities of sports activities on oral health in children.