Biomedical subjects

Timothy J McDonnell

Publications and source records attributed to Timothy J McDonnell.

43 records · Page 3Linked to original sources

PubMed2002

BAX expression in Hodgkin and Reed-Sternberg cells of Hodgkin's disease: correlation with clinical outcome.

PURPOSE: BAX, a proapoptotic member of the BCL-2 family of proteins, has been detected in Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's disease (HD), but its clinical significance is unknown. Therefore, we correlated BAX expression with presenting features and clinical outcome in untreated patients with HD. DESIGN: Patients with biopsy-proven HD were eligible if they were untreated previously and if pretreatment paraffin-embedded tumor tissue was available. BAX was detected by immunohistochemistry without knowledge of clinical features or outcome. A tumor was considered as positive if any number of HRS cells expressed BAX, but other cutoffs of BAX expression were examined for analysis of clinical outcome. RESULTS: We identified 260 patients with HD. The median age was 31 years, and 55% were male. HRS cells expressed BAX in 181 of 195 (93%) nodular sclerosis, 47 of 48 (98%) mixed cellularity, 1 case of lymphocyte depletion, all 6 unclassified classical HD, and all 10 lymphocyte predominance tumors. Using a cutoff of 50% positive HRS cells for BAX expression, the 5-year failure-free survival (FFS) for patients with high versus low BAX expression was 83 versus 93%, respectively (P = 0.19 by Log-rank) for 116 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens; it was 78 versus 79%, respectively, for 79 patients treated with mitoxantrone, vincristine, vinblastine, and prednisone and radiotherapy (P = 0.45 by Log-rank); it was 71 versus 81%, respectively, for 26 patients treated with nitrogen mustard, vincristine, prednisone, and procarbazine (P = 0.6 by Log-rank); and it was 72 versus 82% for 29 patients treated only with radiotherapy (P = 0.57 by Log-rank). The 5-year FFS was not statistically different when we used cutoffs of 20, 30, and 75% for BAX expression. CONCLUSION: BAX is often expressed by HRS cells in HD and does not correlate with FFS.

Adolescent↗

PubMed2002

The association of p21((WAF-1/CIP1)) with progression to androgen-independent prostate cancer.

The molecular events leading to progression toward androgen-independent prostate cancer (AIPC) are not fully understood. The p21((WAF-1/CIP1)) (p21) gene has been identified as a key factor for the regulation of cell growth. The expression of p21 was examined by immunohistochemical studies in 105 prostate cancer samples: (a) 7 of 30 (23%) androgen-dependent tumors; and (b) 36 of 75 (48%) androgen-independent tumors stained positive for p21 (P < 0.02). No association was found between p21 expression and p53, bcl-2, and the androgen receptor protein expression in bone metastases of patients with AIPC, whereas there was a significant association with a high Ki-67 index (P < 0.05). In 4 of 43 (9%) cases, tumors displayed a p53-negative, bcl-2-negative, and p21-positive phenotype. A xenograft mouse model of prostate cancer using the androgen-responsive MDA PCa 2b prostate cancer cell line was used to study p21 expression after androgen deprivation and at relapse. Androgen deprivation reduced p21 expression to undetectable levels after 14 days. Tumor relapse, defining AIPC, was associated with increased expression of p21 to levels comparable with those found before castration. In this model, p21 expression at relapse was also correlated with a high Ki-67 index. In conclusion, p21 expression is associated with the progression to AIPC. A possible explanation involves a paracrine effect of p21 mediated by the release of mitogenic and antiapoptotic factors. Another explanation involves the regulation of p21 expression by the androgen receptor, which also suggests that p21 may have antiapoptotic function in prostate cancer.

Androgens↗

PubMed2002

The application of molecular techniques to solid tumors.

Recent developments in the field of molecular biology including the sequencing of the human genome and related high throughput methodologies are presenting the diagnostic pathologist with new opportunities to expand our understanding of human disease. These techniques enable the comprehensive assessment of molecular alterations with cell populations of interest, including cancer. It will be necessary for the diagnostic pathologist to become familiar with these techniques to effectively translate their potential into the clinical environment.

DNA, Neoplasm↗

PubMed2002

TAD: a web interface and database for tissue microarrays.

Tissue microarrays are increasingly important tools that bring high-throughput technology to traditional pathology laboratories. In many cases, each spot on a tissue microarray is scored by a skilled pathologist and recorded manually. TAD consists of an Active Server Page web interface to a relational database that automates recording scores and linking them with clinical data for future interpretation. TAD is an open source application that can be installed locally.

Computational Biology↗

PubMedDate not supplied

Effectiveness of pulmonary rehabilitation in restrictive lung disease.

BACKGROUND: Pulmonary rehabilitation is effective in improving exercise endurance and quality of life in chronic obstructive pulmonary disease (COPD). However, the efficacy of pulmonary rehabilitation in restrictive lung disease has not been extensively studied. METHODS: Forty-six patients with restrictive lung disease (35 interstitial lung diseases, 11 skeletal abnormalities) were admitted to a pulmonary rehabilitation program; 26 completed the 8-week program and 15 were followed to a 1-year reassessment. Fifteen noncompliant patients were excluded and 1 patient with interstitial lung disease died at 8 weeks. Pulmonary function tests, exercise endurance, quality of life (Chronic Respiratory Disease Questionnaire, St. George's Respiratory Questionnaire, Hospital Anxiety and Depression scale and dyspnea) were measured at baseline, 8 weeks, and 1 year. RESULTS: Exercise endurance (treadmill) improved at 8 weeks (mean improvement, 10.2 +/- 7.4 minutes) and at 1 year (mean improvement, 8.7 +/- 12.2 minutes). Shuttle test improved at 8 weeks (mean improvement, 27.2 +/- 75.9 m) but not at 1 year. Patients using long-term oxygen therapy (LTOT) had a better improvement in the treadmill test (P < .01) at 8 weeks compared with those not using LTOT. Thirty-three percent of patients failed to complete the program. There was significant improvement in dyspnea and quality of life in Chronic Respiratory Disease Questionnaire, St. George's Respiratory Questionnaire, and Hospital Anxiety and Depression scale for depression at 8 weeks compared with baseline; there was a sustained significant reduction in hospital admission days noted at 1-year postrehabilitation (P < .05). CONCLUSIONS: Pulmonary rehabilitation is effective in improving exercise endurance and the quality of life and in reducing hospital admissions in this small group of patients with significant restrictive lung disease. The relatively large dropout number suggests that a standard chronic obstructive pulmonary disease program may not be ideal for patients with restrictive lung disease.

Aged↗

PubMedDate not supplied

Immunosuppressant-responsive idiopathic lymphocytic pleuritis.

Lymphocyte-dominant pleural inflammation is seen in tuberculous, malignant and immune-mediated pleural disease. We describe two male patients who presented with chest pain and dyspnoea, in whom radiological and histological investigations showed idiopathic lymphocytic pleuritis that responded to immunosuppressive therapy with corticosteroids and/or azathioprine. Corticosteroid-responsive pleuritis has been described in association with many conditions, but little is known of idiopathic lymphocytic pleuritis. The authors suggest that patients with idiopathic pleural thickening undergo early thoracoscopic pleural biopsy, and that immunosuppressant therapy be considered for patients with idiopathic lymphocytic pleuritis.

Aged↗

PubMedDate not supplied

A recombinant adenovirus expressing wild-type Bax induces apoptosis in prostate cancer cells independently of their Bcl-2 status and androgen sensitivity.

Using a binary co-transfection strategy of Ad/GT Bax and Ad/PGK-GV16, we have succeeded in inducing overexpression of Bax protein in three prostate cell lines (androgen-insensitive DU145 and PC3, and androgen-sensitive LNCaP). The expression of Bax protein by this system was sufficient to induce all three prostate lines to undergo apoptosis. The fact that DU145 cells which have a p53 mutation and are deficient in Bax, responded to this treatment, suggests that this effect is independent of these pathways. Initiation of the cleavage of Caspase-3 (CPP32/Yama/apopain) and PARP (poly (ADP-ribose) polymerase) by the introduction of Bax were confirmed by western blot analysis. Bcl-2 expression is relevant in the progression of prostate cancer and contributes to an androgen, apoptotic-resistant phenotype in the advanced stages. We examined stable Bcl-2 overexpressing DU145, PC3 and LNCaP cell lines as models of advanced prostate cancer. The adenoviral co-transfection system induced Bax protein expression and apoptosis even in these Bcl-2 transfected cell lines. Taken together, our results suggest that this Bax expression system might represent a useful gene therapy strategy when applied to the treatment of prostate cancer and its efficacy would be independent of the Bcl-2 status and androgen sensitivity of these cancers.

Adenoviridae↗