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C Condron

Publications and source records attributed to C Condron.

17 recordsLinked to original sources
PubMed2005

Anaplastic (undifferentiated) thyroid cancer: improved insight and therapeutic strategy into a highly aggressive disease.

BACKGROUND: This review article discusses the clinical and diagnostic implications of anaplastic thyroid cancer, recognizing the aggressive nature of the disease and extensive disease progression upon diagnosis. Standard treatment strategies (surgical, chemotherapy, radiation) are discussed, comparing adjuvant and neo-adjuvant regimens and the emergence of tumour resistance with expression of multidrug resistance pumps. We question the pathological evolution of anaplasia as a 'de novo' disease or a post malignant transformation or dedifferentiation and the therapeutic implications of p53 mutation. Future treatment options are reviewed with an emphasis on specific molecular targets responsible for the neoplastic phenotype. METHOD: An electronic search on Medline and Pubmed was performed under 'anaplastic thyroid carcinoma', 'anaplastic thyroid carcinogenesis', 'anaplastic thyroid carcinoma treatment reviews'. Relevant papers were systematically reviewed from 1965 to present.

Aged↗
PubMed2003

Neutrophil bactericidal function is defective in patients with recurrent urinary tract infections.

Urinary tract infection (UTI), most frequently caused by Escherichia coli, is one of the most common bacterial infections in humans. It is a host inflammatory response to bacterial invasion in which large numbers of neutrophils are recruited into the bladder in response to cytokines secreted by the infected bladder epithelium. We hypothesise that an impaired host neutrophil response leads to susceptibility to recurrent UTI (rUTI). Therefore, the neutrophil inflammatory response of patients with a history of rUTI was compared to healthy controls. No difference in neutrophil adhesion receptor expression or complement receptor expression following bacterial stimulus was detected between the two groups. However, the expression of the IgG receptor CD16, bacterial phagocytosis and reactive oxygen intermediate (ROI) production were significantly reduced in UTI patient neutrophils compared to controls. Neutrophils from rUTI patients have a significantly reduced bactericidal function when compared to healthy controls, with the former showing a reduced capacity for activation. This reduced neutrophil function may result in defective bacterial clearance and lead to susceptibility to recurrent infection.

Adult↗
PubMed2002

Diethylmaleate, a pro-oxidant, attenuates experimental ischaemia-reperfusion-induced lung injury.

BACKGROUND: Systemic ischaemia-reperfusion (IR) injury is in part an oxidant injury mediated by neutrophils. Diethylmaleate (DEM), an intracellular pro-oxidant agent, has been shown to alleviate neutrophil-mediated tissue injury. The aim of this study was to evaluate whether DEM could have a protective effect on neutrophil-mediated lung injury in an animal model of lower-torso IR. METHODS: Sprague-Dawley rats (seven per group) were randomized into three groups. The control group underwent midline laparotomy only; the IR group underwent laparotomy and clamping of the infrarenal abdominal aorta for 30 min followed by 2 h of reperfusion; and the third group was pretreated with DEM 6 mmol/kg intraperitoneally 1 h before the IR insult. RESULTS: IR resulted in a significant increase in both microvascular leakage and pulmonary neutrophil infiltration as measured by bronchoalveolar lavage protein concentration and pulmonary myeloperoxidase activity respectively. Pretreatment with DEM significantly attenuated both microvascular leakage and neutrophil infiltration. CONCLUSION: Preconditioning with DEM protected against IR-induced lung injury. This protective effect raises the possibility of using pro-oxidants to prevent inflammatory injury.

Animals↗
PubMed2002

A reduction in serum cytokine levels parallels healing of venous ulcers in patients undergoing compression therapy.

INTRODUCTION: vascular endothelial growth factor (VEGF) and tumour necrosis factor alpha (TNF(alpha)) have been specifically implicated in the tissue damage associated with chronic venous disease (CVD). Furthermore, production of both factors is known to be upregulated in vessel wall cells subject to hypertension. The aim of this study was to determine the local venous levels of VEGF and TNF(alpha) in limbs with venous ulcers before and after treatment with graduated compression. PATIENTS AND METHODS: eight patients with venous ulcers and 8 patients with varicose veins only were included in the study. For ulcer patients, serum samples were taken from the superficial veins in lower limbs and repeated after 4 weeks of treatment with 4-layered graduated compression. Serum from the arms of the same patients served as controls. Determination of the concentrations of VEGF and TNF(alpha) proteins were performed with sandwich enzyme-linked immunosorbent assays. RESULTS: both groups of patients had elevated levels of VEGF and TNF(alpha). In patients with venous ulcers there was a reduction in the levels of both cytokines to below control values with treatment. These changes correlated with healing of the ulcers as determined by reduction in ulcer size. CONCLUSION: these data, for the first time, suggest a central role for both TNF(alpha) and VEGF in the pathogenesis of venous ulceration which may constitute a causative link between venous hypertension and tissue pathology.

Aged↗
PubMed2001

Immune function, telomerase, and angiogenesis in patients with primary, operable nonsmall cell lung carcinoma: tumor size and lymph node status remain the most important prognostic features.

BACKGROUND: Lung carcinoma usually is advanced at the time of presentation and frequently shows metastatic spread. In recent times, prognostic factors such as c-erbB-2 in patients with breast carcinoma have provided useful information and beneficial therapeutic targets. The objective of this study was to evaluate angiogenesis, immune function, and telomerase expression in patients with nonsmall cell lung carcinoma (NSCLC) to determine their prognostic significance. METHODS: Immunohistochemistry was used to evaluate the expression of human telomerase reverse transcriptase (hTERT; n = 115 patients), interleukin-2r (IL-2r; n = 40 patients), microvessel density (MVD; n = 81 patients), and vascular endothelial growth factor (VEGF; n = 61 patients). Three-year survival follow-up information was available for most patients, and a comprehensive review of clinicopathologic features was carried out. RESULTS: Fifty percent of tumors showed nuclear staining for hTERT, 55% of tumors showed some degree of lymphocyte IL-2r expression, 33% of tumors were recorded with an MVD that was higher than average, and VEGF staining was detected in 85% of tumors. None of the parameters measured had an impact on survival. hTERT expression was correlated with lymph node status. Lymph node status and tumor size were identified as independent prognostic factors. CONCLUSIONS: This study failed to identify a marker of prognosis for patients with NSCLC other than tumor size and lymph node status in this population. Telomerase expression was associated with metastases, raising the possibility that this enzyme is involved in the metastatic process. Tumor cell VEGF expression was identified frequently: This growth factor may have potential as a target for antiangiogenic therapy. Lung carcinoma typically is the result of large numbers of mutations. Further understanding of the biologic implications of these mutations will lead to the development of effective prognostic markers and treatments for patients with NSCLC.

Adult↗
PubMed2001

Effect of intravenous taurine on endotoxin-induced acute lung injury in sheep.

OBJECTIVE: To find out if pretreatment with taurine would reduce the severity of endotoxin-induced acute lung injury in a large animal model. DESIGN: Randomised controlled study under licence from the Department of Health. SETTING: Department of Surgical Research, Ireland. ANIMALS: 15 male Suffolk sheep. INTERVENTIONS: Vascular catheters were placed in the femoral artery and vein and a Swan-Ganz catheter in the external jugular vein under general anaesthetic. Animals were randomized into three groups: control with measurements taken at baseline and half hourly up to 90 minutes; endotoxin, given Escherichia coli endotoxin intravenously after baseline measurements and taurine given 300 mg/kg 1 hour before endotoxin was given. MAIN OUTCOME MEASURES: Mean systemic arterial pressure, mean pulmonary arterial pressure, arterial oxygen tension (PO2), pulmonary myeloperoxidase activity, and neutrophil respiratory burst activity. RESULTS: Endotoxin induced a severe lung injury characterised by a decrease in mean systemic blood pressure and an increase in pulmonary artery pressure, hypoxia, and an increase in pulmonary myeloperoxidase activity. Pretreatment with intravenous taurine significantly reduced these haemodynamic changes. It reduced pulmonary myeloperoxidase activity and peripheral neutropenia and increased neutrophil respiratory burst activity. CONCLUSIONS: This data suggest that taurine may have a therapeutic role in preventing the lung injury seen in endotoxaemia.

Animals↗
PubMed2001

Human neutrophils facilitate tumor cell transendothelial migration.

Tumor cell extravasation plays a key role in tumor metastasis. However, the precise mechanisms by which tumor cells migrate through normal vascular endothelium remain unclear. In this study, using an in vitro transendothelial migration model, we show that human polymorphonuclear neutrophils (PMN) assist the human breast tumor cell line MDA-MB-231 to cross the endothelial barrier. We found that tumor-conditioned medium (TCM) downregulated PMN cytocidal function, delayed PMN apoptosis, and concomitantly upregulated PMN adhesion molecule expression. These PMN treated with TCM attached to tumor cells and facilitated tumor cell migration through different endothelial monolayers. In contrast, MDA-MB-231 cells alone did not transmigrate. FACScan analysis revealed that these tumor cells expressed high levels of intercellular adhesion molecule-1 (ICAM-1) but did not express CD11a, CD11b, or CD18. Blockage of CD11b and CD18 on PMN and of ICAM-1 on MDA-MB-231 cells significantly attenuated TCM-treated, PMN-mediated tumor cell migration. These tumor cells still possessed the ability to proliferate after PMN-assisted transmigration. These results indicate that TCM-treated PMN may serve as a carrier to assist tumor cell transendothelial migration and suggest that tumor cells can exploit PMN and alter their function to facilitate their extravasation.

Adenocarcinoma↗
PubMed2001

TGF-beta1 is elevated in breast cancer tissue and regulates nitric oxide production from a number of cellular sources during hypoxia re-oxygenation injury.

Cellular response to treatment is dependent on the metabolic preconditioning of individual cells, which is a reflection of environmental conditions. Within solid tumours there are areas of different oxygen tension, which, we hypothesise, may indicate that cells are exposed to conditions that change continually. Other characteristics of the solid-tumour microenvironment include the production of growth factors, one of which is transforming growth factor (TGF)-beta1. As part of this study, we measured TGF-beta1 and found it raised in the serum of breast cancer patients compared with controls (98.24+/-13.25 vs. 48.87+/-12.14 ng/mL; P < 0.05; n = 7), and in the conditioned medium of breast tumour explant tissue compared with matched normal tissue (21.1+/-5.3 vs. 4.7+/-1.2 ng TGF-beta1/gram of tissue; P < 0.05; n = 11). Nitric oxide (NO) is a cytotoxic molecule produced by a large number of cells and thought to have antimetastatic properties. In order to observe the effect of conditions within breast tumours on NO production, we exposed macrophages, endothelial cells and tumour cells to hypoxia re-oxygenation in vitro, both in the presence and absence of TGF-beta1. Hypoxia stimulated increased NO production in both macrophages (normoxia: 0.34+/-0.04 nmol/L nitrite vs. hypoxia: 1.04+/-0.18 nmol/L nitrite; P < 0.05) and endothelial cells (normoxia: 0.02+/-0.01 nmol/L nitrite vs. hypoxia: 0.21+/-0.07 nmol/L nitrite; P < 0.05). NO production in macrophages, endothelial cells and tumour cells was reduced significantly following hypoxia in the presence of TGF-beta1 in a concentration-dependent manner. These results suggest that, within breast tumours, tumour-derived TGF-beta1 in combination with environmental conditions may result in decreased local NO production, which could have implications for tumour growth.

Breast Neoplasms↗
PubMed1999

Vitamin C reduces ischaemia-reperfusion-induced acute lung injury.

OBJECTIVES: to evaluate vitamin C supplementation in the prevention of ischaemia-reperfusion (I-R) induced acute lung injury. DESIGN: Sprague-Dawley rats (n =6/group) were randomised into Control, I-R and I-R pretreated with vitamin C (3.3 g over 5 days). Ischaemia-reperfusion injury was induced by 30 minutes infrarenal aortic cross-clamping and 120 minutes reperfusion. METHODS: pulmonary microvascular injury was measured by broncho-alveolar lavage protein concentration, pulmonary neutrophil infiltration by tissue myeloperoxidase activity and bronchoalveolar lavage neutrophil counts. In a second experiment (n =5/group) neutrophil respiratory burst activity was measured in Control and vitamin C groups. RESULTS: ischaemia-reperfusion resulted in a significant increase in both microvascular leakage and pulmonary neutrophil infiltration as measured by bronchoalveolar lavage protein concentration and pulmonary myeloperoxidase activity respectively. Pretreatment with vitamin C significantly attenuated both microvascular leakage and neutrophil infiltration. Neutrophil respiratory burst activity was significantly reduced in the vitamin C group (13.02 m.c.f.+/-0.3) compared with Control (19.04 m.c.f.+/-1. 9),p <0.02. CONCLUSION: these data suggest that oral vitamin C therapy protects against ischaemia-reperfusion-induced acute lung injury, possibly by attenuating neutrophil respiratory burst activity.

Animals↗
PubMed1999

Involvement of tyrosine protein kinase in IFN-gamma-induced human endothelial cell apoptosis.

Although it is well recognized that interferon-gamma (IFN-gamma) is involved in the development of systemic inflammatory response syndrome, a condition characterized by loss of endothelial barrier function, whether or not IFN-gamma has any direct effect on endothelial cell (EC) death is unclear. Furthermore, which signal transduction pathway involved in IFN-gamma-induced EC apoptosis remains to be elucidated. To answer these questions, we investigated the effect of IFN-gamma on EC death (apoptosis versus necrosis) and the underlying signal transduction pathway responsible for IFN-gamma-induced EC apoptosis. IFN-gamma resulted in a dose-dependent increase in EC apoptosis after 24 h incubation (p < .05). However, IFN-gamma did not induce EC necrosis. Tumor necrosis factor-alpha (TNF-alpha), but not lipopolysaccharide (LPS), had a augmentative effect on IFN-gamma-induced EC apoptosis (p < .05), while both of them alone failed to induce EC apoptosis. These results indicate that exposure of EC to IFN-gamma can cause apoptosis rather than necrosis. Both calcium ionophore, A23187, and the protein kinase C (PKC) activator phorbol-myristate-acetate (PMA) had a synergistic effect on IFN-gamma-induced EC apoptosis (p < .05). However, neither the calcium chelator 1,2-bis 2-aminophenoxy ethane-N,N,N',N'-tetraacetic acid (BAPTA), nor the PKC inhibitor 1 -5-isoquinolinysulfonyl 2-methyl piperazine (H-7) attenuated IFN-gamma-induced EC apoptosis. Three specific tyrosine protein kinase (TPK) inhibitors, herbimycin A, tyrphostin, and genistein, significantly inhibited IFN-gamma-induced EC apoptosis in a dose-dependent fashion (p < .05). Furthermore, the activation of TPK in EC by IFN-gamma was completely abrogated by these TPK inhibitors. These findings suggest that the signal transduction pathway required for induction of EC apoptosis by IFN-gamma is TPK dependent and is independent of calcium and PKC.

Adult↗
PubMed1999

Phenotyping of immune cell infiltrates in breast and colorectal tumours.

White cell infiltration of solid tumors is an important prognostic indicator in malignant disease. Although macrophage infiltration is associated with good outcome in colorectal cancer, a high macrophage content is associated with poor prognosis in breast cancer. Suppressor macrophages prevent T cell activation in normal tissues such as mucosal linings exposed to continuous antigenic challenge. Interleukin 10 (IL-10), an immunosuppressive cytokine, inhibits macrophage co-stimulation of T cells. Suppressor macrophage numbers, T cell numbers and T cell activation status were assessed in cell suspensions obtained from fresh specimens of breast and colorectal tumours and matched normal tissues. IL-10 production by both malignant and matched normal tissue was also assessed. This study identified elevated numbers of suppressor macrophages in breast tumors compared to matched normal breast tissue. Colorectal tumors did not contain significant numbers of these cells. Although T cell numbers are increased in breast tumors, these cells do not appear to be fully activated, as assessed by major histocompatibility complex class II and Interleukin 2 receptor expression. In contrast, T cells in colorectal tumors exhibit greater expression levels of these markers. Breast tumors produce significantly higher levels of IL-10 than normal breast tissue whereas IL-10 levels in colorectal tumors are similar to normal colon tissue. Our findings of high suppressor macrophage numbers, high levels of IL-10 and poorly activated T cells in breast tumors compared to low suppressor macrophage numbers, low IL-10 and fully activated T cells in colorectal tumors may explain why high macrophage content is associated with poor prognosis in breast cancer and good prognosis in colorectal malignancy.

Adult↗
PubMed1996

Neutrophils undergo apoptosis following ingestion of Escherichia coli.

Apoptosis is a distinct mechanism by which eukaryotic cells die. Neutrophils (PMN) play a fundamental role in the systemic inflammatory response syndrome. Clearance of PMN during resolution of the acute inflammatory process occurs by apoptosis, but factors inducing this process are unknown. The aims of this study were to determine whether PMN ingestion of Escherichia coli would result in PMN apoptosis and whether the mechanism was related to the respiratory burst. PMN from 10 healthy volunteers were cultured with different ratios of PMN:E. coli (1:0 to 1:25) for 12 h. Apoptosis was then assessed by propidium iodide DNA staining, morphology, gel electrophoresis, and Fc gamma RIII expression. There was a significant induction of PMN apoptosis on incubation with E. coli at a ratio of 1:10 and 1:25 PMN:E. coli as well as decreases in Fc gamma RIII. This correlated with increased ingestion of FITC-labeled E. coli and intracellular reactive oxygen intermediates after a 2-h coculture. To clarify the role of reactive oxygen intermediates in E. coli-induced PMN apoptosis, we assessed the effects of the antioxidants catalase, DMSO, glutathione, and N-acetylcysteine. There was a significant decrease in E. coli-induced PMN apoptosis on incubation with DMSO (1.0%), glutathione (25 mM), and N-acetylcysteine (25 mM) compared with control PMN:E. coli. This study demonstrates for the first time that E. coli induces PMN apoptosis through an oxygen-dependent mechanism. The removal of effete PMN by the process of apoptosis rather than necrosis may be teleologically beneficial during Gram-negative septicemia.

Antioxidants↗
PubMed1996

The beneficial effect of taurine on the prevention of human endothelial cell death.

This study was designed to test the hypothesis that the antioxidant taurine may modulate human endothelial cell (EC) death (apoptosis versus necrosis). Sodium arsenite (80 microM) alone and in combination with tumor necrosis factor-alpha (25 ng/mL) caused EC apoptosis after 24 h of treatment. Taurine (.5 mg/mL) added at 0 and 6 h could significantly attenuate EC apoptosis, and oxidative state in response to lipopolysaccharide and tumor necrosis factor-alpha stimulation. EC necrosis was induced by activated neutrophils (PMNs). Taurine reduced PMN-mediated EC necrosis in a dose-dependent manner. Moreover, treatment of ECs with a calcium ionophore, A23187 (1.0-4.0 microM), resulted in both EC apoptosis and necrosis. Taurine significantly abrogated A23187-mediated intracellular calcium elevation and EC death. These data indicate that taurine, possibly through its antioxidant activity and regulation of intracellular calcium flux, can prevent EC dysfunction and cell death, which may have implications for the application of this amino acid in the amelioration of acute lung injury during systemic inflammatory response syndrome.

Apoptosis↗
PubMed1995

Induction of heat shock protein 72 prevents neutrophil-mediated human endothelial cell necrosis.

OBJECTIVE: To examine the hypothesis that induction of heat shock proteins in human endothelial cells (ECs) by either heat shock or sodium arsenite could prevent subsequent EC necrosis induced by activated human polymorphonuclear neutrophil leukocytes (PMNs). DESIGN: Cultures of ECs were exposed to heat shock (42 degrees C, 30 to 60 minutes) or sodium arsenite (40 to 320 mumol/L) for 6 hours to induce the expression of a heat shock protein of 72-kd molecular weight (HSP-72). Activated PMNs were subsequently added to these ECs for 24 hours to evaluate the ability of HSP-72 to prevent activated PMN-mediated EC necrosis. RESULTS: Neither EC necrosis nor apoptosis was induced by heat shock. Sodium arsenite (40 to 80 mumol/L) did not induce EC necrosis, although 320-mumol/L sodium arsenite caused a significant increase in EC necrosis. Sodium arsenite (80 to 320 mumol/L) also induced dose-dependent EC apoptosis. Endothelial cells exposed to heat shock and sodium arsenite (40 and 80 mumol/L) significantly attenuated subsequent EC necrosis induced by activated PMNs. However, sodium arsenite at 320 mumol/L aggravated activated PMN-mediated EC necrosis. Expression of HSP-72 was detected after ECs were treated both with heat shock and sodium arsenite (40 to 320 mumol/L) for 6 hours. CONCLUSION: Induction of HSP-72 in ECs by a thermal or nonthermal mechanism could prevent activated PMN-mediated EC necrosis, which may favor increased vascular permeability during systemic inflammatory response syndrome.

Apoptosis↗
PubMed1994

Immune function in patients undergoing open vs laparoscopic cholecystectomy.

BACKGROUND: Abnormal release of inflammatory mediators following surgical injury is associated with immunological alteration, which may predispose to sepsis. Laparoscopic surgery is associated with reduced postoperative complications, but mechanisms are unclear. We hypothesized that early recovery following laparoscopic surgery may relate to minimal impairment of immune function. DESIGN: Analysis of the temporal immune responses in two similar groups of patients randomized to open (n = 22) vs laparoscopic (n = 22) cholecystectomy. Patients were matched for age, height, weight, and operation time. Immune parameters, including monocyte superoxide anion (O2-) and tumor necrosis factor release, neutrophil O2- levels and chemotaxis, total white blood cell counts, partial arterial oxygen pressure, and serum cortisol and C-reactive protein levels were assessed preoperatively and on postoperative days 1 and 3. RESULTS: There were significant increases (P < .001) in monocyte release of O2- and tumor necrosis factor, neutrophil release of O2- and chemotaxis, and white blood cell count in the open vs laparoscopic cholecystectomy study groups, with a concommitant decrease in partial arterial oxygen pressure. These findings correlated with significantly higher postoperative septic complications in the open cholecystectomy group (P < .05). There were no significant differences in either plasma cortisol or C-reactive protein levels between groups. All measurements were carried out in a blinded fashion. CONCLUSIONS: This study demonstrates that laparoscopic surgery appears to be associated with similar metabolic responses compared with open surgery, while immune parameters vary greatly between groups. The beneficial effects of laparoscopic surgery may relate, in part, to preservation of immune function in the postoperative period.

Adult↗
PubMedDate not supplied

Potentiation of the therapeutic index of interleukin-2 immunotherapy by combination with taurine in a syngeneic murine tumour model.

BACKGROUND: Administration of interleukin-2 (IL-2) is limited by the induction of the vascular leak syndrome (VLS). AIMS: To examine the effect of taurine on the toxicity and antitumour activity of IL-2 in a B16 melanoma pulmonary metastases model. METHODS: B16 melanoma cells were injected into female C57BL/6 mice. Macroscopic melanoma pulmonary foci were established by day 10 in untreated mice. Treated mice were randomised into treatment by rIL-2 alone, rIL-2 plus taurine or taurine alone. Control animals received saline. Mice were sacrificed on day 18. Lung metastases were counted in a blinded fashion with the aid of a dissecting microscope. Wet to dry lung weight was measured following lung removal. In another experiment animals were treated as above (n = 15 per group) and survival following treatment monitored. RESULT: Treatment with IL-2 and taurine significantly reduced lung nodules compared with IL-2 alone. Host survival was significantly enhanced. The wet to dry (w/d) ratios of lung weights in the group receiving IL-2/taurine were significantly less than IL-2 alone. Bronchoalveolar lavage protein fluid was reduced indicating reduced pulmonary injury. CONCLUSION: These findings indicate that the combination of taurine with IL-2 augments the efficacy of this immunotherapy while reducing its associated dose-limiting toxicity.

Animals↗