The degree of lymphocyte infiltration is a prognostic factor in liver cancer, but to date the mechanisms by which lymphocytes infiltrate into and are retained in hepatic tumours are poorly understood. We hypothesised that the extracellular matrix glycoprotein vitronectin, a major component of the stroma of hepatic tumours, might play a role in the recruitment and retention of tumourinfiltrating lymphocytes (TIL). Thus, we investigated the ability of vitronectin to support migration and adhesion of TIL isolated from hepatocellular carcinoma and colorectal hepatic metastases. Soluble vitronectin-induced dose-dependent migration of TIL in in vitro chemotaxis and haptotaxis assays and vitronectin in tissue sections was able to support TIL adhesion to tumour stroma. Neither adhesion nor migration was inhibited by a function blocking mAb against the major vitronectin receptor avb3 and we were unable to detect avb3 on TIL in vitro or in vivo on tumour tissue. However, TIL did express high levels of urokinase-type plasminogen activator receptor (uPAR) and inhibitory antibodies and amiloride both significantly inhibited TIL adhesion to vitronectin and reduced transendothelial migration of lymphocytes across liver endothelium in vitro. Thus, we provide evidence that vitronectin in liver tumours can support the recruitment and retention of effector lymphocytes by an uPAR-dependent mechanism.
We propose a data envelopment analysis (DEA)-based approach to ranking multi-criteria alternatives. We call it "the area of the efficiency score graph" (AES) approach. Unlike the classical DEA score and Dk measure that counts the number of DMUs (alternatives in DEA terminology) that should be removed from the set for each DMU k to become efficient, AES is not fully dependent on relative values of inputs/outputs of the alternatives in the set. It considers the change in efficiency scores of the alternatives while we delete 0,…,Dk number of alternatives from the set. The method avoids the negative effect of outliers and crowding in certain areas. It favors DMUs that manage to improve their efficiency scores quickly as we delete units from the set, and also alternatives that maintain high levels of efficiency scores as we delete units. We propose inclusion of weight restrictions into AES to incorporate decision maker preferences into the analysis. We apply our approach to ranking MBA programs. We provide rank lists of MBA programs by both AES and another DEA-based method for comparison. We also use AES scores to place programs in a small number of classes that are preference ordered from the best to the worst.
Background: Expression of the IL-7R␣ gene is up-/down-regulated during T/B-lymphocyte development. Results: IL-7R␣ gene transcription is repressed by the transcription factor Gfi1, specifically in CD8 ϩ T-lymphocytes. Conclusion:Treatment by dexamethasone down-regulates Gfi1, which contributes to glucocorticoid receptor mediated upregulation of IL-7R expression. Significance: The mechanism by which the IL-7R gene gets turned on and off during development is a critical issue in biology. Interleukin-7 receptor ␣ (IL-7R␣) is essential for T cell survival and differentiation. Glucocorticoids are potent enhancers of IL-7R␣ expression with diverse roles in T cell biology.Here we identify the transcriptional repressor, growth factor independent-1 (Gfi1), as a novel intermediary in glucocorticoid-induced IL-7R␣ up-regulation. We found Gfi1 to be a major inhibitory target of dexamethasone by microarray expression profiling of 3B4.15 T-hybridoma cells. Concordantly, retroviral transduction of Gfi1 significantly blunted IL-7R␣ up-regulation by dexamethasone. To further assess the role of Gfi1 in vivo, we generated bacterial artificial chromosome (BAC) transgenic mice, in which a modified Il7r locus expresses GFP to report Il7r gene transcription. By introducing this BAC reporter transgene into either Gfi1-deficient or Gfi1-transgenic mice, we document in vivo that IL-7R␣ transcription is up-regulated in the absence of Gfi1 and down-regulated when Gfi1 is overexpressed. Strikingly, the in vivo regulatory role of Gfi1 was specific for CD8 ؉ , and not CD4 ؉ T cells or immature thymocytes. These results identify Gfi1 as a specific transcriptional repressor of the Il7r gene in CD8 T lymphocytes in vivo.
Aetiology-dependent combinations of adhesion molecules and chemokines expressed within tissue during ALF recruit lymphocytes with a distinct homing phenotype.
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