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Biomedical subjects

T McDonnell

Publications and source records attributed to T McDonnell.

16 recordsLinked to original sources
PubMed2001

Angiogenic potential of prostate carcinoma cells overexpressing bcl-2.

BACKGROUND: Tumors commonly outgrow their blood supply, thereby creating hypoxic conditions, which induce apoptosis and increase expression of angiogenic growth factors. The bcl-2 oncogene inhibits apoptosis induced by a variety of stimuli, including hypoxia. On the basis of bcl-2's role in regulating apoptosis in response to hypoxia, we hypothesized that this oncogene might affect other responses to hypoxia, such as the expression of angiogenic growth factors. METHODS: Three prostate carcinoma cell lines, PC3, LNCaP, and DU-145, were stably transfected with a bcl-2 complementary DNA (cDNA), and transfectants were analyzed in vitro for the expression of angiogenic factors after exposure to either normoxic (19% O(2)) or hypoxic (1% O(2)) conditions. The in vivo angiogenic potential of the transfected cells was determined by analyzing vessel density in xenografts derived from them and by measuring the ability of these xenografts to induce neovascularization when implanted in mouse corneal micropockets. Statistical tests were two-sided. RESULTS: When exposed to hypoxic conditions, prostate carcinoma cells overexpressing bcl-2 expressed statistically significantly higher levels of vascular endothelial growth factor (VEGF), an angiogenic factor, than control-transfected cells (P = .001 for PC3, P = .04 for DU-145 after 48 hours). This effect of bcl-2 was independent of its antiapoptotic activity because increased expression of VEGF was detected in PC3 cells overexpressing bcl-2 even though PC3 cells are inherently resistant to hypoxia-induced apoptosis. In vivo, xenograft tumors derived from the bcl-2-overexpressing prostate carcinoma cell lines displayed increased angiogenic potential and grew more aggressively than tumors derived from the control cell lines (P =.03 for PC3). Treatment of bcl-2-overexpressing and control tumors with the antiangiogenic drug TNP-470 neutralized the aggressive angiogenesis in bcl-2-overexpressing tumors (P = .04 for PC3, P = .004 for DU-145) and the moderate angiogenesis in control tumors (P = .01 for PC3, P = .05 for DU-145), resulting in similar growth rates for both tumors. CONCLUSIONS: bcl-2 may play a dual role in tumorigenesis by suppressing apoptosis and by stimulating angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2001

Adenovirus-mediated Bak gene transfer induces apoptosis in mesothelioma cell lines.

OBJECTIVE: Conventional treatment for mesothelioma is largely ineffective. We therefore evaluated the novel approach of adenoviral gene transfer of the proapoptotic Bcl-2 family member Bak in mesothelioma cancer cell lines, which are sensitive and resistant to adenoviral p53. METHODS: Binary adenoviral Bak (Ad/GT-Bak and Ad/GV16) and LacZ (Ad/GT-LacZ and Ad/GV16) vectors were used for transduction of the mesothelioma cell lines I-45 (p53 resistant) and REN (p53 sensitive). Protein levels were determined by Western blotting. Apoptosis was assessed by morphologic changes, caspase-3 cleavage, and fluorescence-activated cell sorter analysis of subdiploid populations. Cell viability was determined with the XTT assay. Statistical analysis was performed with analysis of variance and the Student t test. RESULTS: High levels of Bak gene transfer were seen after coadministration of Ad/GT-Bak and Ad/GV16 in both mesothelioma cell lines. Apoptosis was induced 24 hours after Bak but not LacZ gene transfer ([Bak: I-45, 36%; REN, 25%] vs [LacZ: I-45, 1%; REN, 3%], P <.05]) in p53-sensitive (REN) and p53-resistant (I-45) cell lines. Cellular viability was significantly decreased 48 to 72 hours after Bak gene transfer compared with control vector in both cell lines (72 hours: Bak I-45, 1.4% +/- 1.0%, and Bak REN, 4.7% +/- 1%, vs Lac-Z I-45, 83% +/- 3%, and Lac-Z REN, 100% +/- 1%; P <.05). CONCLUSIONS: Adenovirus-mediated overexpression of the Bak gene induces apoptosis and decreased cellular viability in p53-sensitive and p53-resistant mesothelioma cells. These data suggest that the gene transfer of proapoptotic Bcl-2 family members may represent a novel gene therapy strategy to treat mesothelioma.

Adenoviridae↗
PubMed1999

The spectrum of mycobacterial disease in a Dublin teaching hospital.

We describe our experience at our combined tuberculosis and public health clinic, which has been in existence since 1991, and compare it to a previous review of tuberculosis at St. Vincent's Hospital from 1974 to 1979. A total of 107 patients were treated, 58 male and 49 female, with a mean age of 53 years. Seventy-seven patients had pulmonary tuberculosis, 23 extrapulmonary and three had both. Four patients had miliary tuberculosis. Our figures reflect the fall in incidence of tuberculosis in Ireland since the 1970's and a rise in smear negative and presumptive cases. The epidemiology of tuberculosis in Ireland is little changed except for an increasing impact of immigration. Problems such as late diagnosis, especially in older patients, and non-compliance remain significant. In addition, there were four deaths from tuberculosis. However, our combined clinic has led to the appropriate management of patients by Respiratory Medicine specialists and a great move to ambulatory diagnosis and management. We believe it is the best model for the effective management of tuberculosis in Ireland.

Adult↗
PubMed1998

New chemotherapy combinations with docetaxel in the treatment of patients with non-small cell lung cancer.

The modest antitumor activity and clinical benefit of conventional platinum-containing multidrug regimens in locally advanced and metastatic non-small cell lung cancer have provided the impetus for the development of novel combinations. The promising single-agent activity of docetaxel makes it an obvious candidate for incorporation into active programs. The Irish Clinical Oncology Research Group is conducting a phase I-II evaluation of a three-drug combination of docetaxel, ifosfamide, and cisplatin with lenograstim support in patients with stages III-IV non-small cell lung cancer. Preliminary results indicate that the regimen is feasible and tolerable up to a maximum tolerated dose level of 3,000 mg/m2 ifosfamide, 75 mg/m2 cisplatin, and 75 mg/ m2 docetaxel. The regimen appears to be quite active, with nine of 12 evaluable patients responding in the phase I component of the trial. This dose level is currently being explored in a phase II trial.

Adult↗
PubMed1996

Flow cytometric analysis of apoptosis and bcl-2 in primary breast carcinomas: clinical and biological implications.

Analysis of programmed cell death (apoptosis), of bcl-2, a critical regulator of this process, and of the proliferative fraction may provide detailed information on the biologic characteristics of tumor cell populations. To investigate the potential role of these parameters in assessing mammary carcinoma, we adapted flow cytometric procedures for concurrent measurement of apoptosis, bcl-2 expression, and cell proliferation in 54 primary breast carcinomas and correlated the findings with traditional clinicopathologic information. Overall, a significant inverse relationship between apoptosis levels and bcl-2 expression was observed (P = 0.005). Apoptosis levels correlated significantly with DNA aneuploidy (P = 0.03) and S + G2M fractions (P = 0.005) of these tumors. A significant correlation between bcl-2 expression and estrogen receptor positivity (P = 0.05) and DNA diploidy (P = 0.02) was noted. Bcl-2 expression, however, was inversely correlated with S + G2M fractions (P = 0.001). We conclude that analysis of apoptosis and bcl-2 by flow cytometry allows further characterization of tumor cell populations that may be useful for prognostic and therapeutic management of breast carcinoma.

Adult↗
PubMed1995

Tuberculin sensitivity and the BCG scar in tuberculosis contacts.

SETTING: Tuberculosis clinic, St Vincents Hospital, Dublin. OBJECTIVE: To determine the influence of past BCG vaccination on tuberculin sensitivity in tuberculosis contacts. DESIGN: Prospective cohort study of tuberculin sensitivity using the Mantoux technique (5 TU). RESULTS: In 1050 contacts of 96 cases of tuberculosis, BCG scars were noted in 76% of the contacts. Approximately 50%, 30% and 20% of the contacts respectively had negative (0-4 mm), positive (5-14 mm) and strongly positive (15+ mm) Mantoux responses. The presence of a BCG scar was not found to significantly influence the degree of tuberculin sensitivity. The degree of tuberculin sensitivity increased after 20 years and decreased after 60 years of age. Contacts of sputum-positive cases of tuberculosis had larger Mantoux responses. CONCLUSIONS: The study suggests that age of the contact and sputum status of the index case are important determinants of the degree of tuberculin sensitivity. Attributing a 'positive' Mantoux response to past BCG vaccination may be encouraging a false sense of security in contacts recently exposed to an infectious case of tuberculosis. Contact management guidelines may need to be reviewed and perhaps modified to reflect this finding.

Adolescent↗
PubMed1994

Differential sensitivity of normal and Ha-ras-transformed C3H mouse embryo fibroblasts to tumor necrosis factor: induction of bcl-2, c-myc, and manganese superoxide dismutase in resistant cells.

In this study, we investigated the role of activated Ha-ras oncogene on the growth-regulatory properties of tumor necrosis factor (TNF) in C3H mouse embryo fibroblasts. TNF-resistant 10T1/2 cells transfected with an activated Ha-ras oncogene not only produced tumors in nude mice but also exhibited extreme sensitivity to cytolysis by TNF. TNF-induced cell death was mediated through apoptosis. The differential sensitivity of normal and Ha-ras transformed cells to TNF was not due to differences in the number of TNF receptors on their cell surface. However, TNF-resistant cells, but not sensitive cells, overexpressed bcl-2, c-myc, and manganese superoxide dismutase (MnSOD) mRNA following exposure to TNF. In addition, TNF treatment resulted in a marginal induction of p53 mRNA in both TNF-sensitive and resistant cells. These results suggest that TNF-induced cytotoxicity involves apoptosis and that TNF-induced over-expression of bcl-2, c-myc, and MnSOD genes is associated with TNF resistance in C3H mouse embryo fibroblasts.

Animals↗
PubMed1989

The fate of bone marrow micrometastases in patients with primary breast cancer.

Using an immunocytochemical technique, micrometastases have been found in the bone marrow of approximately 26% of patients with primary breast cancer at the time of initial surgery. To determine the fate of these cells, both in patients receiving and not receiving adjuvant therapy, multiple bone marrow aspirates were repeated in 82 patients at a median time of 18 months after surgery but prior to overt relapse. In both treated and untreated patients micrometastases were only found in one of 45 (2%) and one of 37 (3%) patients, respectively. However, when multiple marrow aspirates were taken from patients with local recurrence the incidence of micrometastases was 19% (three of 16), and this increased to 30% (three of ten) in patients with disease at distant sites other than bone, and 100% (ten of ten) in patients with radiologically proven bony disease. Three of 11 (27%) patients in whom the primary tumor remained in situ while receiving adjuvant therapy before definitive surgery had micrometastases at the time of diagnosis and at follow-up 3 months later. These results suggest that many of the micrometastases from breast cancer patients are the result of "shedding" of cells from the primary carcinoma and that a proportion are not viable. The technique is currently insufficiently sensitive to accurately monitor adjuvant therapy in breast cancer patients.

Antineoplastic Agents↗
PubMed1988

Automated screening for micrometastases in bone marrow smears.

It is possible to detect micrometastases in primary breast cancer using immunocytochemical staining of bone marrow smears. However, using the light microscope the procedure is time-consuming and laborious because such cells occur rarely (less than 1 in 10,000). Using an image analysis system, the Leytas machine, and a specially prepared reproducible slide it has been possible to automate the technique. A 100% concordance was found between the machine and the light microscope in the identification of slides containing moderate to high numbers of tumour cells in bone marrow, and in those containing no tumour cells. However, in those slides containing low numbers of tumour cells (1-10 tumour cells/10(6) normal bone marrow cells) the sensitivity was decreased to 91%. In the presence of non-specific staining the false positive rate was increased from 0% to 22%. This method represents a potential improvement in the assessment of an important clinical staging procedure.

Bone Marrow↗
PubMed1988

Malignant fibrous histiocytoma of the lung.

Malignant fibrous histiocytoma (MFH) is among the most common soft tissue sarcomas of adult life, but rarely occurs elsewhere. We report an example of primary MFH of the lung and review 15 previously reported acceptable cases with current follow-up information. Histologically, the tumor in our case was pleomorphic with storiform and fascicular areas. Tumor cells showed positive immunostaining for alpha 1-antitrypsin, alpha 1-antichymotrypsin, and vimentin. Stains for desmin, cytokeratin, myoglobin, epithelial membrane antigen, S-100 protein, and lysozyme were negative. Electron microscopic study showed histiocyte-like, fibroblast-like, intermediate, and undifferentiated tumor cells. A variety of methods were used to treat these patients. Two patients survived for 5 or more years, two were alive and well at 8 and 12 months, respectively, two were alive with metastatic tumor at 3 and 18 months, respectively, and ten patients died of tumor, with an average survival of 1 year.

Aged↗
PubMed1987

Micrometastases in bone marrow in patients with primary breast cancer: evaluation as an early predictor of bone metastases.

The bone marrow of 307 patients with primary breast cancer was examined for tumour cells by immunocytochemistry using an antiserum to epithelial membrane antigen. Micrometastases were found in 81 cases (26.4%) and their presence was related to various poor prognostic factors: spread to lymph nodes, vascular invasion, T stage, and pathological size. The median duration of follow up was 28 months. Seventy five patients relapsed, 60 at distant sites. Of these 60 patients, 26 had micrometastases detected at presentation and 34 were free of micrometastases initially. The relapse free interval was significantly shorter for patients with micrometastases, and these patients had a shorter survival. Analysis of the sites of relapse showed that the test predicted bone metastases only. Thus 10 out of 19 patients (53%) who developed bone metastases at first relapse had micrometastases at presentation compared with only 41 out of 288 patients (14%) who remained free of bone metastases or relapsed in non-skeletal sites. The presence of micrometastases detected at the time of initial surgery in a patient with primary breast cancer is a useful predictor of early relapse in bone and may help in selecting patients for subsequent systemic treatment.

Adult↗
PubMed1987

Upper airway obstruction during sleep in normal subjects after selective topical oropharyngeal anesthesia.

Previous animal studies support the presence of an upper airway reflex mechanism that when blocked by topical anesthesia of the upper airway results in upper airway occlusion. We sought a similar reflex mechanism in humans. Nine normal male volunteers 20 to 28 yr of age underwent 3 successive overnight sleep studies: a control study (C); a study in which selective topical oropharyngeal anesthesia (OPA) was achieved prior to sleep using a 10% lidocaine spray and 0.25% bupivocaine solution; a study in which selective nasal anesthesia (NA) was achieved prior to sleep using a mixture of 2% lidocaine and 0.25% bupivocaine solutions instilled into the nose while the nasal airway was positioned as the most dependent part of the upper airway. Total sleep times were similar during the 3 study nights as were the amounts of slow-wave and rapid-eye-movement (REM) sleep. Obstructive apneas and hypopneas (OAH) differed significantly between the 3 study nights [13(3.8), mean (SEM), during OPA as compared to 3(1.8) during C and 7(2.5) during NA; p less than 0.01 by ANOVA] and were most frequent during REM sleep. Total apneas and hypopneas also differed significantly between the 3 study nights [19(3.9) during OPA as compared to 8(2.1) during C and 14(3.9) during NA; p less than 0.01 by ANOVA]. Movement arousals terminating periods of abnormal respiration also differed significantly [21(6.1) during OPA as compared to 12(3.6) during C and 14(4.6) during NA; p less than 0.05 by ANOVA]. No subject, however, developed clinically significant sleep apnea or significant oxygen desaturation during sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Nocturnal nasal intermittent positive pressure ventilation (NIPPV) therapy for chronic respiratory failure: long-term effects.

The development of positive pressure ventilation delivered through a nasal or face mask has greatly expanded the use of non-invasive ventilation in patients with chronic respiratory insufficiency, particularly during sleep. Disorders ranging from neurologic and neuromuscular, such as polio and muscular dystrophy, central alveolar hypoventilation, thoracic cage disorders such as kyphoscoliosis, and pulmonary disorders such as COPD, particularly of the blue-bloater type. The relative hypoventilation that is common to each condition is due to varying combinations of an inadequate respiratory drive and an increase in the work of breathing. Previous studies have shown sustained reversal of awake hypercapnia in patients with alveolar hypoventilation syndrome using nocturnal NIPPV. We analysed 10 consecutive patients with chronic respiratory insufficiency due to diverse aetiologies over a period of time using long-term domiciliary nocturnal NIPPV. Awake hypercapnia and hypoxaemia improved in nine patients over time and deteriorated in one patient. There was no significant change in pulmonary function apart from one patient with progressive muscular dystrophy who deteriorated. A considerable reduction in the need for subsequent hospital admission was noted in the group as a whole following institution of NIPPV. We conclude that nocturnal NIPPV improves awake gas exchange in patients with chronic respiratory failure.

Carbon Dioxide↗