9 research outputs found
Exploiting a Bacterial Drug‐Resistance Mechanism: A Light‐Activated Construct for the Destruction of MRSA
No full textAuthor correction: High-dose chemotherapy and autologous stem cell transplantation in enteropathy-associated and other aggressive T-cell lymphomas: a UK NCRI/Cancer Research UK Phase II Study (Bone Marrow Transplantation, (2019), 54, 3, (465-468), 10.1038/s41409-018-0294-2)
No full text In the original version of this article, the mention of ‘ifosfamide 1500 mg/m 2 days 1–3’ should, in fact, read ‘ifosfamide 1500 mg/m 2 bd days 1–3’. This has now been updated in the original version of the article. </p
Exploiting a Bacterial Drug‐Resistance Mechanism: A Light‐Activated Construct for the Destruction of MRSA
No full textF11-Receptor (F11R/JAM) Mediates Platelet Adhesion to Endothelial Cells: Role in Inflammatory Thrombosis
No full textSummaryThe F11 receptor (F11R) is a cell adhesion molecule (CAM), member of the immunoglobulin superfamily found on the surface of human platelets, and determined to play a role in platelet aggregation, secretion, adhesion and spreading. The same molecule is present also at tight junctions of endothelial cells (EC) where it is known as JAM and acts as a CAM through homophilic interactions. The role of F11R/JAM in the interaction of platelets with endothelial cells was investigated in the current studies. We report here that washed human platelets adhere specifically to a matrix made of immobilized, recombinant sF11R. Furthermore, platelets adhere to cytokine(TNF-α, INF-γ) stimulated human umbilical vein endothelial cells (HUVEC), and approximately 40-60% of the adhesive force is exerted by homophilic interactions between the F11R of platelets and EC. This is evidenced by the inhibition of platelet adhesion to endothelial cells by recombinant soluble form of the F11R, and by two F11R peptides with amino acid sequences of the N-terminal region, and in the 1st Ig fold of the F11R, respectively. This study suggests a role for F11R in the adhesion of platelets to cytokine-inflamed endothelial cells and thus in thrombosis and atherosclerosis induced in non-denuded blood vessels by inflammatory processes. Agents that block the F11R-mediated adhesion of platelets to EC may be of therapeutic value in controlling thrombosis and preventing heart attacks and stroke.</jats:p
Two Regions of the Human Platelet F11-Receptor (F11R) Are Critical for Platelet Aggregation, Potentiation and Adhesion
No full textSummaryThe F11 receptor (F11R) was first identified on the surface of human platelets as a target for a stimulatory monoclonal antibody (M.Ab.F11) that induces secretion, followed by exposure of fibrinogen receptors and aggregation. Cloning of the gene of F11R has revealed that this protein is a cell adhesion molecule (CAM), a member of the Ig superfamily and an ortholog of the murine protein called junctional adhesion molecule (JAM). The present study has identified two domains through which M.Ab.F11 triggers a platelet response culminating with aggregation. M.Ab.F11-mediated platelet adhesion, and the potentiation of collagen and ADP-induced platelet aggregation by M.Ab.F11, were found to involve the same two domains. A F11R recombinant protein (sF11R) completely inhibited platelet aggregation, adhesion and potentiation induced by M.Ab.F11, indicative that the active conformation of the external domain of F11R is present in the soluble, secreted recombinant protein. Furthermore, a specific peptide containing the sequence of the N-terminal amino acids S-1 to C-23 of F11R, and a peptide with the sequence of K-70 to C-82 in the 1st immunoglobulin-like (Ig) fold of F11R, both inhibited M.Ab.F11-induced aggregation, adhesion and potentiation of the aggregation of human platelets. Modeling of the 3D structure of the extracellular domain of the human platelet F11R suggests that these two regions form an active site within the conformation of this CAM. The sequence of these functional domains of F11R (in the N-terminus and 1st Ig-fold) provide the basis for new drug development in the treatment of certain types of thrombocytopenia and inflammatory thrombosis.</jats:p
Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases.
No full textBACKGROUND
Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases.
METHODS
We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes.
FINDINGS
Two shared clusters, CXCL10CCL19 immune-interacting and SPARCCOL3A1 vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation.
CONCLUSIONS
This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases.
FUNDING
Grant from F. Hoffmann-La Roche (Roche) AG
