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Biomedical subjects

D J O'Connor

Publications and source records attributed to D J O'Connor.

At least 19 recordsLinked to original sources
PubMed2001

ASPP proteins specifically stimulate the apoptotic function of p53.

We identified a family of proteins termed ASPP. ASPP1 is a protein homologous to 53BP2, the C-terminal half of ASPP2. ASPP proteins interact with p53 and specifically enhance p53-induced apoptosis but not cell cycle arrest. Inhibition of endogenous ASPP function suppresses the apoptotic function of endogenous p53 in response to apoptotic stimuli. ASPP enhance the DNA binding and transactivation function of p53 on the promoters of proapoptotic genes in vivo. Two tumor-derived p53 mutants with reduced apoptotic function were defective in cooperating with ASPP in apoptosis induction. The expression of ASPP is frequently downregulated in human breast carcinomas expressing wild-type p53 but not mutant p53. Therefore, ASPP regulate the tumor suppression function of p53 in vivo.

Apoptosis↗
PubMed2000

Stress signals induce transcriptionally inactive E2F-1 independently of p53 and Rb.

One of the common features of cellular response to stress is cell cycle arrest or apoptosis. E2F is one of the key factors which controls cell cycle progression. Overexpression of E2F-1 can also induce apoptosis. In order to understand the role of E2F-1 in cellular response to stress, we studied the E2F-1 response in various cell lines to different types of stress signals including UV irradiation, cisplatin, etoposide and hypoxia. We showed here that the expression level of E2F-1 can be up regulated by the treatment of DNA damage agents as well as hypoxia. The kinetics of E2F-1 increase was dependent on the types of inducer and was similar to that of p53. However, stress signals can induce E2F-1 expression independently of p53 and Rb. Furthermore, the induced E2F-1 was transcriptionally inactive. All these results suggested that E2F-1 may play a very important role in cellular response to stress and this novel role of E2F-1 is independent of its transactivation function.

Carrier Proteins↗
PubMed2000

Randomized, controlled study of low-dose 5-fluorouracil in primary trabeculectomy.

PURPOSE: To report a randomized clinical trial of postoperative subconjunctival injections of low-dose 5-fluorouracil in patients undergoing primary trabeculectomy. METHODS: In a prospective, randomized clinical trial, 40 eyes of 40 patients were randomized to the low-dose 5-fluorouracil group and received three subconjunctival injections of 5 mg each over 11 postoperative days, and 40 eyes of 40 patients were randomized to trabeculectomy without 5-fluorouracil. RESULTS: Mean (+/-SD) preoperative and 1-year postoperative intraocular pressures in the 5-fluorouracil group were 26.9 (+/-9.5) and 15.3 (+/-5.8) mm Hg, respectively. In the control group these were 25.9 (+/-8.1) mm Hg, and 15.8 (+/-5.1) mm Hg, respectively. The patients who received 5-fluorouracil had a mean reduction in intraocular pressure of 11.5 (+/-9.1) mm Hg at a median follow-up of 52.3 weeks. The control group had a mean reduction in intraocular pressure of 10.2 (+/-8.7) mm Hg at a median follow-up of 52.6 weeks. These differences were not statistically significant. CONCLUSIONS: Three postoperative subconjunctival 5-fluorouracil injections of 5 mg each after trabeculectomy in eyes at low risk for failure had no statistically or clinically significant effect on reduction of intraocular pressure with 1-year follow-up. Enhancement of success in this group of patients may require a larger total dose of 5-fluorouracil.

Adult↗
PubMed2000

Proapoptotic p53-interacting protein 53BP2 is induced by UV irradiation but suppressed by p53.

p53 is an important mediator of the cellular stress response with roles in cell cycle control, DNA repair, and apoptosis. 53BP2, a p53-interacting protein, enhances p53 transactivation, impedes cell cycle progression, and promotes apoptosis through unknown mechanisms. We now demonstrate that endogenous 53BP2 levels increase following UV irradiation induced DNA damage in a p53-independent manner. In contrast, we found that the presence of a wild-type (but not mutant) p53 gene suppressed 53BP2 steady-state levels in cell lines with defined p53 genotypes. Likewise, expression of a tetracycline-regulated wild-type p53 cDNA in p53-null fibroblasts caused a reduction in 53BP2 protein levels. However, 53BP2 levels were not reduced if the tetracycline-regulated p53 cDNA was expressed after UV damage in these cells. This suggests that UV damage activates cellular factors that can relieve the p53-mediated suppression of 53BP2 protein. To address the physiologic significance of 53BP2 induction, we utilized stable cell lines with a ponasterone A-regulated 53BP2 cDNA. Conditional expression of 53BP2 cDNA lowered the apoptotic threshold and decreased clonogenic survival following UV irradiation. Conversely, attenuation of endogenous 53BP2 induction with an antisense oligonucleotide resulted in enhanced clonogenic survival following UV irradiation. These results demonstrate that 53BP2 is a DNA damage-inducible protein that promotes DNA damage-induced apoptosis. Furthermore, 53BP2 expression is highly regulated and involves both p53-dependent and p53-independent mechanisms. Our data provide new insight into 53BP2 function and open new avenues for investigation into the cellular response to genotoxic stress.

Apoptosis↗
PubMed1999

RB regulates the stability and the apoptotic function of p53 via MDM2.

The binding of RB to MDM2 is shown to be essential for RB to overcome both the antiapoptotic function of MDM2 and the MDM2-dependent degradation of p53. The RB-MDM2 interaction does not prevent MDM2 from inhibiting p53-dependent transcription, but the RB-MDM2 complex still binds to p53. Since RB specifically rescues the apoptotic function but not the transcriptional activity of p53 from negative regulation by MDM2, transactivation by wild-type p53 is not required for the apoptotic function of p53. However, an RB-MDM2-p53 trimeric complex is active in p53-mediated transrepression. These data link directly the function of two tumor suppressor proteins and demonstrate a novel role of RB in regulating the apoptotic function of p53.

Apoptosis↗
PubMed1999

The biological response of MCF7 breast cancer cells to proteosome inhibition or gamma-radiation is unrelated to the level of p53 induction.

The p53 tumour suppressor is stabilised following exposure to genotoxic agents, such as gamma-radiation. Cell responses to p53 stabilisation include induction of apoptosis and/or cell cycle arrest. Several studies have suggested that gamma-radiation stabilises p53 by blocking ubiquitin mediated proteolysis. Here we have compared the biological activities of p53 stabilized following exposure to gamma-radiation or treatment with the proteosome inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (ALLN) in MCF7 cells with wild type p53. Stabilisation of p53 by ALLN was reversible and was not blocked by caffeine. Although ALLN was a more effective p53 stabilising agent than gamma-radiation, ALLN was not as effective at inducing cell cycle arrest/apoptosis as gamma-radiation. Although p53 stabilised by ALLN and gamma-radiation were both able to bind DNA and activate transcription, ALLN did not increase expression of BAX, which is involved in p53-induced apoptosis. Therefore, p53 stabilised by different agents is not always biologically active to the same extent and additional alterations triggered by gamma-radiation may enable p53 to activate a subset of critical target genes, such as BAX, which are required for p53 responses.

Journal Article↗
PubMed1999

Continuing the search for WBGT clothing adjustment factors.

The original concept for the heat stress limits adopted by the American Conference of Governmental Industrial Hygienists (ACGIH) was that the threshold for heat stress can be marked by environmental conditions (WBGT) that are adjusted for metabolic rate. The underlying data were based on ordinary work clothes. The Physical Agents Committee promoted clothing adjustment factors within the industrial hygiene community through a revision in the TLVs for heat stress in 1990. As approved, there were adjustment factors for three other clothing ensembles. To extend and further understand adjustment factors, adjustments for commercially available clothing ensembles and prototype ensembles have been examined. The fundamental principle of the assignment of an adjustment factor to an ensemble begins with establishing critical environmental conditions in which test subjects were just able to maintain thermal equilibrium. Four or five subjects for each ensemble walked on a tread-mill inside a climatic chamber under controlled conditions of heat stress. During each test, heart rate and core temperature were continuously monitored. After a physiological steady-state was achieved, temperature and humidity were slowly increased to maintain relative humidity at 20 percent, 50 percent, or 70 percent. Metabolic rate was assessed by measuring the rate of oxygen consumption. Reviewing a trial, the critical conditions were noted as the time when thermal regulatory control was lost (called the inflection point and marked by a steady increase in core temperature). The climatic conditions at the inflection point were used to assign a critical WBGT. A WBGT representative of each ensemble was assigned through a weighted average of different protocols. Clothing adjustment factors representing an equivalent increase in WBGT were computed by noting the difference between the representative WBGT of the cotton work clothes and the other clothing ensembles. The results suggested adjustment factors with reference to ordinary work clothes from the least stress at -2.1 to 5.5 degrees C-WBGT. The adjustment factors were reasonably well predicted by a linear regression based on a computed value for total evaporative resistance (r2 = 0.92).

Adult↗
PubMed1995

Physical and functional interactions between p53 and cell cycle co-operating transcription factors, E2F1 and DP1.

One way in which wild-type p53 is able to regulate cell cycle progression is thought to be via the induction of its downstream target gene Waf1/CIP1, thus indirectly regulating the transcriptional activity of E2F. The E2F transcription factors are known to be key effectors of the cell cycle. We report here that there is a physical and functional interaction between p53 and two of the components of the E2F transcription factors, E2F1 and DP1. The expression of wild-type p53 can inhibit the transcriptional activity of E2F, and the expression of both E2F1 and DP1 can also downregulate p53-dependent transcription. The transcriptional activity of p53 is known to be inhibited by the direct binding of mdm2, but we demonstrate here that both E2F1 and DP1 can inhibit p53 transcriptional activity independently of mdm2. Detailed studies of protein-protein interactions have provided evidence that E2F1 and its co-operating factor DP1 can complex with p53 both in vitro and in vivo.

Animals↗
PubMed1993

Comparisons of methods to detect glaucomatous optic nerve damage.

PURPOSE: Various techniques of optic disc and nerve fiber layer evaluation may be used to detect structural glaucomatous damage. The authors compared several qualitative and quantitative methods to determine their relative sensitivities and specificities to detect the presence of glaucomatous visual field loss. METHODS: Fifty-one healthy eyes, 169 ocular hypertensive eyes with normal visual fields, and 132 glaucomatous eyes with early visual field defects were evaluated with qualitative and quantitative measures of structural damage to the optic nerve and nerve fiber layer. Qualitative evaluations were performed by three experienced masked observers who independently graded stereoscopic color disc and monochromatic nerve fiber layer photographs. Quantitative measurements of disc rim area and nerve fiber layer height were made with digitized image analysis of videographic images. Manual planimetric measurements of disc rim area were made from enlarged prints of stereoscopic optic disc photographs. Diagnostic precision was defined as the total proportion of correct diagnoses for the presence or absence of visual field loss. RESULTS: The diagnostic precision of results of a quantitative disc examination (81%) was greater than those of a qualitative nerve fiber layer examination (75%). Quantitative nerve fiber height measurement had the highest sensitivity rate (73%) and results of the qualitative disc examination had the highest specificity rate (87%) of the methods tested. CONCLUSION: The diagnostic precision of disc evaluation was superior to other methods, including nerve fiber layer examination, in correctly determining the presence of structural glaucomatous damage at the early visual field loss stage.

Adult↗
PubMed1992

A surgical method to repair leaking filtering blebs.

Surgical revision of a chronically-thinned filtering bleb with a leak at the limbus is described. After surgical excision of the scarred cystic conjunctiva and Tenon's fascia surrounding the leaking bleb, relatively uninvolved conjunctiva and Tenon's fascia are mobilized with the help of a large relaxing incision in the superior fornix and sutured over the area of filtration. We have used this technique successfully in five cases to provide fresh tissue to repair the bleb leak and restore adequate filtration.

Conjunctival Diseases↗
PubMed1991

"Idiopathic" deep venous thrombosis: the value of routine abdominal and pelvic computed tomographic scanning.

Recent studies have demonstrated an increased incidence in the diagnosis of malignancy subsequent to the diagnosis of deep venous thrombosis or pulmonary embolus. We reviewed 237 patients with venographically proven deep venous thrombosis over eight years. Of these, 216 had at least one predisposing cause for deep venous thrombosis; of the remaining 21 patients, three had hemoglobin determinations revealing anemia and were subsequently shown to have a malignant disease. One patient had two chief complaints and was shown to have deep venous thrombosis and malignant disease. The 17 remaining patients underwent computed tomographic scan of the abdomen and seven (41%) had abnormalities which proved to be malignant in origin. One further patient was diagnosed with carcinoma of the cervix two months following the onset of deep venous thrombosis. The remaining 10 patients continued free of malignant disease. Five have died of circulatory causes in the follow-up period. Seven of the nine patients diagnosed with malignancy succumbed within six months of the diagnosis. We conclude that only a small group of patients with deep venous thrombosis will have no identifiable cause for deep venous thrombosis and be asymptomatic for malignancy. Complete blood count, physical examination and computed tomographic scan of the abdomen at the time of venographic diagnosis of deep venous thrombosis is useful in diagnosis of "occult" malignancy. The number of gynecologic tumors would suggest the need for pelvic examination as well as radiographic examination. The presence of deep venous thrombosis and malignant disease is an ominous prognostic sign.

Abdominal Neoplasms↗
PubMed1980

Poxvirus and multiple tumors in an eastern gray squirrel.

A moribund juvenile gray squirrel (Sciurus carolinensis) with numerous skin fibromas was submitted to the Northeastern Research Center for Wildlife Diseases. Necropsy revealed multiple firm white nodules in the lungs. On histologic examination, in addition to the skin lesions, fibromatous proliferations were seen in the wall of the alimentary tract, in 1 mesenteric lymph node, and in the myocardium. Tubular adenomas were seen in the renal cortex, and the lung nodules were bronchoalveolar adenomas. Eosinophilic intracytoplasmic poxvirus inclusion bodies were seen in both the mesenchymal and epithelial tumors.

Adenoma↗
PubMed1979

Staphylococcus aureus mastitis in nursing mink affected with aleutian disease.

An outbreak of staphylococcal mastitis in nursing female ranch mink (Mustela vison) is described. Lesions were acute necrotizing mastitis, fatty infiltration of the liver and renal tubules, and adrenal cortical hyperplasia. The presence of Aleutian disease in the herd suggests a role of immunosuppression in the outbreak.

Aleutian Mink Disease↗
PubMed1978

The moderately repetitive DNA sequences of Caenorhabditis elegans do not show short-period interspersion.

In these studies we show that the moderately repetitive DNA sequences of Caenorhabditis elegans are not arranged in the characteristic short-period interspersion pattern of most eukaryotes. Rather, the moderately repetitive sequences are arranged in long arrays as in Drosophila and Apis. These findings indicate that this type of arrangement is more phylogenetically diverse and hence less exceptional than previously believed.

Animals↗
PubMed1976

Computed tomography in a community hospital.

Computed tomography may be effectively utilized in the radiology department of a community hospital. An ideal program features regional services, 7-day, 24-hour coverage, immediate response to emergencies, prompt reporting, and availability of ancillary hospital services. Experience indicates that early scanning may eliminate the need for invasive diagnostic procedures, prevent or shorten hospital stay, and minimize the morbidity and expense of neuroradiological diagnosis.

Adult↗