Summary~/8 T cells can be grouped into discrete subsets based upon their expression of T cell receptor (TCR) variable (V) region families, their tissue distribution, and their specificity. V~2 + T cells constitute the majority of~/8 T cells in peripheral blood whereas V81 + T cells reside preferentially in skin epithelium and in the intestine. ~/~ T cells are envisioned as first hne host defense mechanisms capable of providing a source of immune effector T cells and immunomodulating cytokines such as interleukin (IL) 4 or interferon (IFN) % We describe here the fine specificity of three distinct ~/~+ tumor-infiltrating lymphocytes (TIL) obtained from patients with primary or metastatic colorectal cancer, that could be readily expanded in vitro in the presence oflL-l~ and IL-7. Irrespective of donor, these individual ~/8 T cells exhibited a similar pattern of reactivity defined by recognition ofautologous and allogeneic colorectal cancer cells, renal cell cancer, pancreatic cancer, and a freshly isolated explant from human intestine as measured by cytolytic T cell responses and by IFN-~/release. In contrast, tumors of akemate histologies were not lysed, including lung cancer, squamous cell cancer, as well as the natural/lymphocyte-activated killer cell-sensitive hematopoietic cell lines T2, CIR, or Daudi. The cell hne K562 was only poorly lysed when compared with colorectal cancer targets. Target cell reactivity mediated by V8I + T cells was partially blocked with Abs directed against the TCR, the [32 or [37 integrin chains, or fibronectin receptor. Marker analysis using flow cytometry revealed that all three ~ T cell lines exhibit a similar phenotype. Analysis of the ~/8 TCR junctional suggested exclusive usage of the V81/D~3/J81 TCtk segments with extensive (~<29 bp) N/P region diversity. T cell recognition of target cells did not appear to be major histocompatibility complex restricted or to be correlated with target cell expression of heat-shock proteins. Based on the ability of some epithehal tumors, including colorectal, pancreatic, and renal cell cancers to effectively cold target inhibit the lysis of colorectal cancer cell lines by these V8I + T cell lines, we suggest that intestinal V~I + T cells are capable of recognizing cell surface Ag(s) shared by tumors of epithehal origin.
While the biomedical informatics community widely acknowledges the utility of domain ontologies, there remain many barriers to their effective use. One important requirement of domain ontologies is that they must achieve a high degree of coverage of the domain concepts and concept relationships. However, the development of these ontologies is typically a manual, time-consuming, and often error-prone process. Limited resources result in missing concepts and relationships as well as difficulty in updating the ontology as knowledge changes. Methodologies developed in the fields of natural language processing, information extraction, information retrieval and machine learning provide techniques for automating the enrichment of an ontology from free-text documents. In this article, we review existing methodologies and developed systems, and discuss how existing methods can benefit the development of biomedical ontologies.
Nitric oxide (NO) is a potent tumor radiosensitizer; however, its clinical use is limited by systemic side effects. We have demonstrated previously that gene transfer of the human inducible NO synthase (iNOS) gene into tumor cells and tumors induces high-output NO production that significantly enhances tumor radioresponsiveness, with no observed side effects. Notably, iNOS gene transfer enhances tumor radioresponsiveness via apoptotic cell death. Because NO and ionizing radiation are both known to promote p53-dependent apoptosis, we hypothesized that p53 activation might be a primary mechanism for the synergy of these two genotoxic stresses. We report that NO and ionizing radiation synergistically activate p53 in colorectal cancers grown in athymic mice by augmenting phosphorylation of p53 at serine 15. The effect of NO and ionizing radiation on tumor cell apoptosis and tumor radioresponsiveness is significantly reduced in p53 knockout isogenic cancer cell lines. Furthermore, the transfer of both p53 and iNOS genes into tumor cells lacking functional p53 enhanced their radioresponsiveness more than transfer of either gene alone.
Studies were undertaken to examine hepatocyte CD14 expression during endotoxemia. Our results show that lipopolysaccharide (LPS) treatment in vivo caused a marked upregulation in CD14 mRNA and protein levels in rat hepatocytes. Detectable increases in mRNA were seen as early as 1.5 h after LPS treatment; these increases peaked at 20-fold by 3 h and returned to baseline levels by 24 h. In situ hybridization localized the CD14 mRNA expression to hepatocytes both in vitro and in vivo. Increases in hepatic CD14 protein levels were detectable by 3 h and peaked at 12 h. Hepatocytes from LPS-treated animals expressed greater amounts of cell-associated CD14 protein, and more of the soluble CD14 was released by hepatocytes from LPS-treated rats in vitro. The increases in hepatocyte CD14 expression during endotoxemia occurred in parallel to increases of CD14 levels in plasma. To provide molecular identification of the hepatocyte CD14, we cloned the rat liver CD14 cDNA. The longest clone consists of a 1,591-bp insert containing a 1,116-bp open reading frame. The deduced amino acid sequence is 372 amino acids long, has 81.8 and 62.8% homology to the amino acid sequences of mouse and human CD14, respectively, and is identical to the rat macrophage CD14. The expressed CD14 protein from this clone was functional, as indicated by NF-κB activation in response to LPS and fluorescein isothiocyanate-LPS binding in CHO cells stably transfected with rat CD14. A nuclear run-on assay showed that CD14 transcription rates were significantly increased in hepatocytes from LPS-treated animals, indicating that the upregulation in CD14 mRNA levels observed in rat hepatocytes after LPS treatment is dependent, in part, on increased transcription. In vitro and in vivo experiments indicated that interleukin-1β and/or tumor necrosis factor α participate in the upregulation of CD14 mRNA levels in hepatocytes. Our data indicate that hepatocytes express CD14 and that hepatocyte CD14 mRNA and protein levels increase rapidly during endotoxemia. Our observations also support the idea that soluble CD14 is an acute-phase protein and that hepatocytes could be a source for soluble CD14 production.
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