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Biomedical subjects

F Shanahan

Publications and source records attributed to F Shanahan.

At least 91 records · Page 5Linked to original sources
PubMed1999

Micrometastases in esophagogastric cancer: high detection rate in resected rib segments.

BACKGROUND & AIMS: Micrometastases within bone marrow indicate a poor prognosis. We prospectively examined micrometastases in patients undergoing resection of esophagogastric cancers for (1) prevalence in rib marrow; (2) comparative detection rates in rib and iliac crest marrow; (3) responsiveness to neoadjuvant therapy; and (4) viability and tumorigenicity. METHODS: In 50 consecutive patients, marrow was obtained before manipulation of the primary tumor. Micrometastatic cells were detected by staining contaminant cytokeratin-18-positive cells. Viability and tumorigenicity were determined by culture and xenograft. RESULTS: Micrometastases were detected in rib marrow from 88% of patients (44 of 50). When bilateral iliac crest marrow was also obtained, micrometastases were found in 15% (4 of 27) compared with 89% (24 of 27) for ribs (P < 0.001). Detection rates were independent of histological type or nodal status and were similar in patients with and without neoadjuvant therapy. Metastatic cells were cultured from rib marrow of 5 of 7 patients and were tumorigenic in nude mice. CONCLUSIONS: Most patients undergoing resection of esophagogastric malignancies have micrometastases in rib marrow. Detection rates based on iliac crest marrow are underestimates. Hematogenous spread of metastatic cells is independent of histological type or nodal status. The metastatic cells are viable, tumorigenic, and resistant to neoadjuvant therapy.

Adenocarcinoma↗
PubMed1999

Invasion by esophageal cancer cells: functional contribution of the urokinase plasminogen activation system, and inhibition by antisense oligonucleotides to urokinase or urokinase receptor.

Early metastasis contributes to the very poor prognosis of esophageal carcinoma. The recent immunohistochemical finding that invasive esophageal carcinomas express elevated levels of urokinase (uPA) and urokinase receptor (uPA-R) in vivo suggest that the plasminogen activation system may contribute to metastasis in esophageal cancer. The aim of our study was to functionally investigate, at the molecular level, the relative contribution of uPA and uPA-R to the invasiveness of esophageal cancer cells in vitro. The three esophageal cancer cell lines, OC1-3, generated in our laboratory, were analyzed for uPA and uPA-R expression by RT-PCR, immunoenzymatic staining, and quantitative ELISA. Invasiveness of all cell lines was quantified as percentage cellular invasiveness in a standardized Matrigel in vitro assay. OC1 and OC3, which were found to coexpress both uPA and uPA-R, displayed stronger invasiveness (44% and 32.5% respectively) relative to OC2 (19%) which expressed uPA-R but was negative for uPA. Transfection of OC2 cells with the uPA cDNA resulted in two variants, OC2.uPA1 and OC2.uPA2, stably expressing functional uPA. Both transfectants exhibited enhanced invasiveness (60% and 50% respectively) relative to the parent uPA-negative OC2 cells (19%). Antisense oligonucleotide inhibition of either uPA or uPA-R expression resulted in a similar, marked reduction in invasiveness of esophageal tumor cells which normally coexpress both molecules (OC1, OC3 and the uPA-expressing OC2-transfectant clones). Neither antisense treatment altered the basal invasiveness of OC2, which expresses uPA-R but not uPA. In conclusion, coexpression of uPA with its receptor, uPA-R, is required for functional involvement of the urokinase system in invasion by esophageal carcinoma cells. Our results suggest that these synergistic mediators of invasiveness are quantitatively major contributors to the invasiveness of esophageal carcinoma.

DNA, Complementary↗
PubMed1999

Fas ligand and Fas receptor are coexpressed in normal human esophageal epithelium: a potential mechanism of apoptotic epithelial turnover.

Fas (CD95/Apo-1) receptor (FasR) is a cell-surface receptor that mediates apoptotic cell death upon triggering by Fas ligand (FasL). We sought to determine whether normal human esophageal epithelial cells express FasL and/or FasR and whether their localization is consistent with a role in the turnover of normal esophageal epithelium. Normal esophageal epithelium was immunohistochemically positive for FasL in upper prickle cell layers and in mature squamous cells, but the proliferative basal layer was negative. FasL mRNA was detected in the same epithelial cell layers by in situ hybridization. Co-localization of FasL mRNA and protein therefore confirmed that FasL expression is induced in esophageal epithelial cells as they reach terminal differentiation. FasR was immunohistochemically detected throughout the esophageal epithelium. Positive TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling) staining confirmed cell death of the FasL and FasR coexpressing mature epithelial cells. CD45-positive immunocytes were notably absent from FasL-expressing upper epithelial layers. The findings are consistent with a contributory role for Fas-mediated autocrine suicide or paracrine fratricide in the apoptotic turnover of normal esophageal epithelium.

Apoptosis↗
PubMed1999

Resistance to Fas (APO-1/CD95)-mediated apoptosis and expression of Fas ligand in esophageal cancer: the Fas counterattack.

The mechanisms by which esophageal tumors escape immunologic recognition and clearance are only partly understood at the molecular level. Esophageal cancers have been shown to evade host recognition by down-regulation of antigen presentation and production of immunosuppressive factors. Recently, two independent reports have shown that esophageal tumor cells abundantly express Fas ligand (FasL) in vivo. As the triggering agonist for Fas receptor (Fas or APO-1/CD95)-mediated apoptosis of lymphocytes, FasL normally plays immune down-regulatory roles, including activation-induced cell death of T and B cells, as well as maintaining immune privilege in certain organs. Fas ligand expressed by esophageal cell lines has been shown to induce apoptosis of cocultured Fas-sensitive lymphoid cells in vitro. FasL expression by esophageal carcinomas in vivo has been associated with significantly reduced tumor-infiltrating lymphocytes (TILs) in FasL-positive tumor nests, concomitant with significantly increased TIL apoptosis in these nests. These studies support a 'Fas counterattack' mechanism of immune escape in esophageal cancer. By expressing functional Fas ligand, esophageal cancer cells can deplete antitumor lymphocytes by inducing apoptosis. To express functional FasL, esophageal carcinomas also acquire molecular mechanisms to resist autocrine Fas-mediated apoptosis of tumor cells.

Apoptosis↗
PubMed1999

Type 1 diabetes mellitus, coeliac disease, and lymphoma: a report of four cases.

INTRODUCTION: Patients with Type 1 diabetes mellitus have a high prevalence of coeliac disease, symptoms of which are often mild, atypical, or absent. Untreated coeliac disease is associated with an increased risk of malignancy, particularly of lymphoma. We describe four patients with Type 1 diabetes mellitus and coeliac disease who developed lymphoma. CASE REPORTS: Two patients were male and two female. In three patients, coeliac disease and lymphoma were diagnosed simultaneously. Enteropathy-associated T cell lymphoma occurred in two patients, Hodgkin's disease in one, and B cell lymphoma in one. Response to treatment was in general poor, and three patients died soon after the diagnosis of lymphoma was made. CONCLUSION: As the relative risk of lymphoma is reduced by a gluten-free diet, a high index of suspicion for coeliac disease should exist in all Type 1 diabetic patients with unexplained constitutional or gastrointestinal symptoms.

Adult↗
PubMed1999

An international survey of the use and attitudes regarding alternative medicine by patients with inflammatory bowel disease.

OBJECTIVE: There is a perception of increasing and widespread use of alternative medicine for inflammatory bowel disease (IBD). We assessed the usage of alternative therapies among patients with IBD, whether there were similar or contrasting variables that were predictive of such use, and contrasted the use in four different centers in North America and Europe. METHODS: Patients in four IBD centers completed a self-administered questionnaire regarding alternative medicine. The centers were in Cork, Los Angeles, Stockholm, and Winnipeg. Patient demographics, the use of 18 types of alternative medicine, and attitudes towards alternative and conventional medicine were compared. A multiple logistic regression analysis was used. RESULTS: Fifty-one percent of 289 patients used some form of alternative medicine. The percentages of use by site were Cork = 31%, Los Angeles = 68%, Stockholm = 32%, and Winnipeg = 57%. The six most commonly used therapies in descending order were: exercise (28%), prayer (18%), counseling (13%), massage (11%), chiropractic (11%), and relaxation (10%). Only 7% used acupuncture or homeopathy and 5% used herbal medicine. The highest odds ratios (confidence intervals [CIs]) for using any form of alternative medicine were associated with: being single 3.1 (1.7-5.7), Los Angeles patient 4.4 (2.3-8.3), Winnipeg patient 2.7 (1.3-5.9), and an increase of alternative medicine use of 2.7% for every M.D. visit (CI, 2-11%/visit). The patient age, gender, disease diagnosis, or duration of disease were not predictive of any type of alternative medicine use. Regarding attitudes, respondents from Cork were most favorable toward alternative medicine use and least favorable toward conventional medicine. Based on attitudes, subjects were more likely to use alternative medicine if they were not satisfied with conventional therapy, viewed hospitals as dangerous places, thought that alternative medicine practitioners should have a role in hospitals, and felt their medical situation was hopeless. CONCLUSIONS: Fifty-one percent of respondents used some form of alternative medicine. The use was greater among the North American patients than the European ones. Respondents were more likely to use alternative medicine if they were single, in a higher income bracket, and an urban dweller.

Attitude↗
PubMed1999

Expression of Fas (CD95/APO-1) ligand by human breast cancers: significance for tumor immune privilege.

Breast cancers have been shown to elicit tumor-specific immune responses. As in other types of cancer, the antitumor immune response fails to contain breast tumor growth, and a reduction in both the quantity and cytotoxic effectiveness of tumor-infiltrating lymphocytes (TILs) is associated with a poorer prognosis. Fas ligand (FasL) induces apoptotic death of activated lymphocytes that express its cell surface receptor, FasR (CD95/APO-1). FasL-mediated apoptosis of activated lymphocytes contributes to normal immune downregulation through its roles in tolerance acquisition, immune response termination, and maintenance of immune privilege in the eye, testis, and fetus. In this report, we demonstrate that breast carcinomas express FasL. Using in situ hybridization and immunohistochemistry, we show that breast tumors constitutively express FasL at both the mRNA and protein levels, respectively. FasL expression is prevalent in breast cancer: 100% of breast tumors (17 of 17) were found to express FasL, and expression occurred over more than 50% of the tumor area in all cases. By immunohistochemistry, FasR was found to be coexpressed with FasL throughout large areas of all the breast tumors. This suggests that the tumor cells had acquired intracellular defects in FasL-mediated apoptotic signaling. FasL and FasR expression were independent of tumor type or infiltrative capacity. FasL expressed by tumor cells has previously been shown to kill Fas-sensitive lymphoid cells in vitro and has been associated with apoptosis of TILs in vivo. We conclude that mammary carcinomas express FasL in vivo as a potential inhibitor of the antitumor immune response.

Breast Neoplasms↗
PubMed1999

Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest.

SWI-SNF complexes have been implicated in transcriptional regulation by chromatin remodeling. We have identified an interaction between two components of the mammalian SWI-SNF complex and cyclin E, an essential cell cycle regulatory protein required for G1/S transition. BRG1 and BAF155, mammalian homologs of yeast SWI2 and SWI3, respectively, are found in cyclin E complexes and are phosphorylated by cyclin E-associated kinase activity. In this report, we show that overexpression of BRG1 causes growth arrest and induction of senescence-associated beta-galactosidase activity, which can be overcome by cyclin E. Our results suggest that cyclin E may modulate the activity of the SWI-SNF apparatus to maintain the chromatin in a transcriptionally permissive state.

Amino Acid Sequence↗
PubMed1999

Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer.

BACKGROUND: Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a "Fas counterattack" against antitumour immune effector cells may contribute to tumour immune escape. AIM: To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer. SPECIMENS: Thirty paraffin wax embedded human gastric adenocarcinomas. METHODS: FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). RESULTS: Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour. CONCLUSIONS: Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer.

Adenocarcinoma↗
PubMed1999

Brain-gut axis and mucosal immunity: a perspective on mucosal psychoneuroimmunology.

The role of the brain-gut axis has traditionally been investigated in relation to intestinal motility, secretion, and vascularity. More recently, the concept of brain-gut dialogue has extended to the relationship between the nervous system and mucosal immune function. There is compelling evidence for a reciprocal or bi-directional communication between the immune system and the neuroendocrine system. This is mediated, in part, by shared ligands (chemical messengers) and receptors that are common to the immune and nervous systems. Although the concept of psychoneuroimmunology and neuroimmune cross-talk has been studied primarily in the context of the systemic immune system, it is likely to have special significance in the gut. The mucosal immune system is anatomically, functionally, and operationally distinct from the systemic immune system and is subject to independent regulatory signals. Furthermore, the intestinal mucosal immune system operates in a local milieu that depends on a dense innervation for its integrity, with juxtaposition of neuroendocrine cells and mucosal immune cells. An overview of evidence for the biologic plausibility of a brain-gut-immune axis is presented and its potential relevance to mucosal inflammatory disorders is discussed.

Adult↗