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Biomedical subjects

R O'Connor

Publications and source records attributed to R O'Connor.

At least 55 records · Page 3Linked to original sources
PubMed1998

Inhibition of tumorigenesis and induction of apoptosis in human tumor cells by the stable expression of a myristylated COOH terminus of the insulin-like growth factor I receptor.

The insulin-like growth factor I receptor (IGF-IR) plays an important role in cell transformation and in protection from apoptosis. Although the wild-type IGF-IR generally has an antiapoptotic effect, there are reports that its COOH terminus may actually generate a proapoptotic signal. Three different expression plasmids, all coding for the COOH-terminal sequences of the human IGF-IR, MyCF, CF, and MyKCF, were stably transfected into human ovarian carcinoma CaOV-3 cells. All three plasmids had no effect on monolayer growth but strongly inhibited colony formation in soft agar. Only one of the plasmids, MyCF, expressing the last 112 amino acids of the IGF-IR and carrying a myristylation signal, caused large-scale apoptosis of CaOV-3 cells in vivo and abrogation of tumorigenesis in nude mice. The plasmid expressing the MyCF sequence was also introduced into human glioblastoma T98G cells, where it decreased the clonogenicity of cells, caused a marked inhibition of colony formation in soft agar, and induced apoptosis in vivo. A double mutation at residues 1293 and 1294 of MyCF completely abrogated its inhibitory and proapoptotic activities. Neither the autophosphorylation of the IGF-IR nor the tyrosyl phosphorylation of IRS-1 was affected by the expression of the MyCF plasmid. These and other findings suggest that a stably expressed myristylated COOH terminus of the IGF-IR can induce apoptosis in human tumor cells in vivo and inhibit tumorigenesis in nude mice by a mechanism that avoids the protective effect of the IGF-IR.

Animals↗
PubMed1998

Dangers of delay of initiation of either thrombolysis or primary angioplasty in acute myocardial infarction with increasing use of primary angioplasty.

We observed treatment delays and suboptimal outcomes when beginning to treat patients with acute myocardial infarction (AMI) with primary angioplasty. Of the 37 patients treated during a 12-month period, 12 (32%) required either emergency bypass surgery or died. Delayed time intervals to balloon reperfusion (mean 134 minutes) probably contributed to these adverse outcomes, with hemodynamic instability requiring pressors or intra-aortic balloon pumping in 15 patients, 12 (75%) before the first balloon inflation. Eleven of the 12 patients with significant adverse outcomes required such intervention. As angioplasty use increased, time intervals to thrombolysis in those not treated with angioplasty increased from an average of 29 minutes (53% treated less than the national standard of 30 minutes) to 39 minutes (32% treated <30 minutes, p <0.001). During the last 2 months of the study period, the time intervals had increased to 48 minutes (14% treated <30 minutes, p <0.0001). There was no change in thrombolytic time intervals at a local community hospital that did not offer primary angioplasty. Emergency Department physician confusion about the best therapy (angioplasty or thrombolysis) was documented in the medical records in 42% of cases (53 of 127). Confusion regarding therapy of AMI led to unacceptable delays in the administration of thrombolytic agents and probably contributed to the adverse outcomes in patients receiving primary angioplasty.

Aged↗
PubMed1998

Expression of the insulin-like growth factor I receptor C terminus as a myristylated protein leads to induction of apoptosis in tumor cells.

The insulin-like growth factor I receptor (IGF-IR) has been shown to mediate mitogenesis and suppression of apoptosis. Certain mutations in the COOH terminus of the receptor abrogate the antiapoptotic activity but not the mitogenic activity. However, truncation of the receptor by deletion of the COOH-terminal 108 amino acids enhances suppression of apoptosis by the IGF-IR, which suggests that the COOH terminus has a negative regulatory role. To investigate this further, a series of mammalian expression vectors were generated that encoded either the COOH terminus of the receptor or the COOH terminus plus the kinase domain. In some cases, the first 16 amino acids of SRC were included at the NH2 terminus to provide a site for myristylation. In transient transfection assays, the membrane-targeted COOH-terminal construct, MyCF, was found to induce apoptosis in MCF-7 breast carcinoma cells and C6 glioblastoma cells, whereas the COOH-terminal construct without the myristylation signal, CF, was poorly cytotoxic. MyKCF, which encodes the kinase domain as well as the COOH terminus, had intermediate cytotoxicity. The cytotoxicity of MyCF was diminished by point mutations that were previously shown to abrogate suppression of apoptosis in the context of the full-length receptor. MCF-7 cells stably expressing the CF or the MyCF proteins exhibited decreased clonogenicity in soft agar and increased sensitivity to UV irradiation. These results indicate that expression of the IGF-IR COOH terminus promotes apoptosis of tumor cells, possibly by interfering with signals necessary for cell survival.

Acylation↗
PubMed1998

Survival factors and apoptosis.

This chapter will explore the role of survival factors in suppression of apoptosis, and illustrate how survival signals play a critical role in the survival of both normal and tumor cells. Survival factors necessary for the development and maintenance of the nervous system and hemopoietic system will be surveyed. This will be followed by a detailed discussion of the role of insulin-like growth factor I (IGF-I) and its receptor in suppression of apoptosis. The importance of survival signals from the IGF-IR for development and tumorigenesis will be discussed, and results of a mutational analysis of the receptor to assign domains necessary for suppression of apoptosis will be summarized. Finally, a discussion of the signal transduction pathways involved in survival factor-signaling will review the roles played by PI-3 kinase and AKT and speculate on how activation of these kinases by survival factors might regulate the apoptotic pathway.

Animals↗
PubMed1997

Perforated duodenal ulcer presenting with shock in a child.

Presentation of peptic ulcer disease in children covers a broad spectrum ranging from subtle, and thus overlooked and underdiagnosed, to catastrophic, as in this case. It is important for the emergency physician to realize the potential morbidity and mortality of this disease and be aware of the spectrum of presentation for primary and secondary pediatric ulcer disease.

Abdomen, Acute↗
PubMed1997

Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis.

Using a series of insulin-like growth factor I (IGF-I) receptor mutants, we have attempted to define domains required for transmitting the antiapoptotic signal from the receptor and to compare these domains with those required for mitogenesis or transformation. In FL5.12 cells transfected with wild-type IGF-I receptors, IGF-I affords protection from interleukin 3 withdrawal but is not mitogenic. An IGF-I receptor lacking a functional ATP binding site provided no protection from apoptosis. However, receptors mutated at tyrosine residue 950 or in the tyrosine cluster (1131, 1135, and 1136) within the kinase domain remained capable of suppressing apoptosis, although such mutations are known to inactivate transforming and mitogenic functions. In the C terminus of the IGF-I receptor, two mutations, one at tyrosine 1251 and one which replaced residues histidine 1293 and lysine 1294, abolished the antiapoptotic function, whereas mutation of the four serines at 1280 to 1283 did not. Interestingly, receptors truncated at the C terminus had enhanced antiapoptotic function. In Rat-1/ c-MycER fibroblasts, the Y950F mutant and the tyrosine cluster mutant could still provide protection from c-Myc-induced apoptosis, whereas mutant Y1250/1251F could not. These studies demonstrate that the domains of the IGF-I receptor required for its antiapoptotic function are distinct from those required for its proliferation or transformation functions and suggest that domains of the receptor required for inhibition of apoptosis are necessary but not sufficient for transformation.

Animals↗
PubMed1997

Disseminated tuberculosis with and without a miliary pattern on chest radiograph: a clinical-pathologic-radiologic correlation.

SETTING: Province of Manitoba, Canada. OBJECTIVE: To describe the characteristics of disseminated tuberculosis (TBD) with and without a miliary pattern on chest radiograph, to determine the mortality, and to identify the demographic and clinical features associated with survival. DESIGN: A retrospective case review. RESULTS: Of 2013 cases of active tuberculosis reported to the Provincial Tuberculosis Registry between January 1979 and December 1993, 56 had disseminated disease. The odds of developing TBD were significantly higher in females. Compared to those with a miliary pattern (n = 42), those without a miliary pattern on chest radiograph (n = 14) were significantly more likely to have a risk factor for tuberculosis (86% vs 52%, P < 0.05) and to die (86% vs 21%, P < 0.001). The diagnosis of TBD was significantly more likely to be made at postmortem in non-miliary compared to miliary patients (43% vs 5%, P < 0.05). Amongst patients with a miliary pattern, the presence of one or more risk factors for tuberculosis was associated with a significantly higher mortality (P < 0.05). Meningitis was very uncommon and did not determine the outcome. CONCLUSION: Disseminated tuberculosis patients without a miliary pattern on chest radiograph have an extremely high mortality rate; those with a miliary pattern may also succumb, especially if co-morbid with a condition known to increase the risk of tuberculosis.

Adult↗
PubMed1996

Determination of serum and tissue levels of phenazines including clofazimine.

A rapid and sensitive HPLC method is described for the analysis of synthetic phenazines, including clofazimine, from a variety of biological samples. Phenazines were extracted from serum, tissue and fat using a mixture of dichloromethane and sodium hydroxide. The drugs were then quantified on a reversed-phase C18 column using a mobile phase consisting of 594 ml of water, 400 ml of tetrahydrofuran, 6 ml of concentrated acetic acid and 0.471 g of hexanesulfonic acid. In this mobile phase, each phenazine tested had its own retention time. This allowed one phenazine to be used as an internal standard for the analysis of other phenazines. The method was validated for clofazimine [3-(4-chloroanilino)-10-(4-chlorophenyl)-2,10-dihydro-2-(isopro pylimino) phenazine] and B4090 [7-chloro-3-(4-chloranilino)-10-(4-chlorophenyl)-2, 10-dihydro-2-(2,2,6,6-tetramethylpiperid-4-ylimino)phenazine ] (VI) and shown to be accurate and precise across a broad concentration range from 0.01 to 50 micrograms/g (microgram/ml). Extraction was 100% for each agent across this range. This system was used to measure clofazimine and VI levels following their administration to rats. The pharmacokinetic profile of VI was different to that of clofazimine, with high tissue concentrations but lower fat levels.

Adipose Tissue↗
PubMed1996

Cure of multidrug-resistant human B-cell lymphoma xenografts by combinations of anti-B4-blocked ricin and chemotherapeutic drugs.

The CD-19-directed immunotoxin anti-B4-blocked ricin (anti-B4-bR) is currently in clinical trials for the treatment of B-cell malignancies. To explore the potential of using anti-B4-bR with chemotherapy protocols we tested the in vivo efficacy of the immunotoxin in combination with two multi-drug chemotherapeutic regimens in severe combined immunodeficient (SCID) mice bearing disseminated tumors of the multidrug-resistant human B-cell lymphoma Namalwa/mdr-1. In cytotoxicity studies in vitro, combinations of the immunotoxin with cisplatin produced supra-additive killing effects on both Namalwa and Namalwa/mdr-1 cells, whereas anti-B4-bR combined with 4-hydroperoxy-cyclophosphamide caused additive killing of both cell lines. In vivo cyclophosphamide, cisplatin, vincristine, doxorubicin, and etoposide as single agents, were effective in prolonging the survival of SCID mice burdened with the Namalwa tumor, whereas only cyclophosphamide and cisplatin were effective on Namalwa/mdr-1 tumors. Treatment of Namalwa/mdr-1-bearing mice with anti-B4-bR alone or with the drug combination CHOE (consisting of cyclophosphamide, vincristine, doxorubicin, and etoposide) alone increased the lifespan of the tumor-burdened mice by 58% and 73%, respectively. However, treatment with five daily bolus intravenous injections of anti-B4-bR followed by CHOE increased the lifespan by 173%, and 20% of the mice were cured. The drug combination CCE (cyclophosphamide, cisplatin, and etoposide) alone could increase the lifespan of the Namalwa/mdr-1 tumor-burdened mice by 129% compared with untreated controls. Combination therapy with anti-B4-bR and CCE produced long-term cures in 50% of the tumor-burdened mice. These results suggest that anti-B4-bR in combination with current multidrug regimens may constitute a highly efficacious modality for the treatment of drug-resistant B-cell malignancies.

Animals↗
PubMed1996

The pharmacokinetics and bioavailability of clemastine and phenylpropanolamine in single-component and combination formulations.

Studies were conducted in healthy male volunteers (n = 171; age range, 19-49 years; 22-27 subjects per study) to examine the following: pharmacokinetics and dose proportionality of the antihistamine clemastine; the effect of coadministration of phenylpropanolamine and clemastine on the pharmacokinetics of the two drugs; and the bioavailability of clemastine tablets and combination tablets of clemastine and sustained-release phenyl-propanolamine under fasted and fed conditions after single-dose administration and at steady state. All studies used crossover designs, with randomized drug treatments separated by a 7-day washout period for the single-dose studies, and with administration every 6 or 12 hours for 7 days per treatment for the steady-state studies. After single oral doses of clemastine solution (1,2, and 4 mg), the area under the concentration-time curve (AUC) and maximum concentration (Cmax) were dose proportional. Clemastine showed a first-pass reduction in the extent of absorption, with oral bioavailability calculated as 39.2 +/- 12.4%. Extravascular distribution of drug was suggested by the high volume of distribution (799 +/- 315 L) and low Cmax (0.577 +/- 0.252 ng/mL/mg) observed at 4.77 +/- 2.26 hours after administration, and by the biphasic decline in plasma concentration. The terminal elimination half-life (t1/2) of clemastine was 21.3 +/- 11.6 hours. Steady-state concentrations of clemastine were consistent with linear pharmacokinetic processes, and clearance was unaffected by age in the range studied, or by race. Clemastine solution and tablets were bioequivalent, and food had no significant effect on rate and extent of absorption of clemastine. The 1- and 2-mg clemastine tablets showed proportional bioavailability. Coadministration of clemastine with phenylpropanolamine did not significantly influence the pharmacokinetics of clemastine or the AUC and elimination t1/2 of phenylpropanolamine, but reduced the rate of absorption of phenylpropanolamine. Combination tablets containing 1 mg or 2 mg of immediate-release clemastine plus 75 mg of sustained-release phenylpropanolamine for twice daily administration were bioequivalent to the separate components and showed no significant interaction with food.

Adult↗
PubMed1996

Trajectories and profiles of adaptive behavior in males with fragile X syndrome: multicenter studies.

We conducted two multicenter studies on adaptive trajectories and profiles in males with fragile X syndrome. Study 1 longitudinally assessed 29 males ages 1-20 years using age-equivalent scores from the Vineland Adaptive Behavior Scales. Fragile X boys ages 1-10 years showed significant gains in adaptive skills from first to second testing; males ages 11-20 years were stable in their adaptive development. Study 2 cross-sectionally examined 132 males ages 1-20 years. Significant age-related gains were found in boys ages 1-10, particularly in preschool children. Subjects ages 11-20 showed increased variability and nonsignificant relations between age and adaptive skills. Preliminary findings from 26 young adults with fragile X syndrome ages 21-40 years showed stable age-equivalent adaptive scores during these years. Relative strengths in daily living skills and weaknesses in communication were only evident among older subjects. Significant relations were found between adaptive behavior standard scores and IQ; these two scores also showed age-related declines that likely parallel one another. Findings are related to adaptive features in other genetic syndromes, and to directions for future adaptive behavior research.

Activities of Daily Living↗
PubMed1995

Anti-B4-blocked ricin synergizes with doxorubicin and etoposide on multidrug-resistant and drug-sensitive tumors.

Anti-B4-blocked ricin (anti-B4-bR) is an immunotoxin directed against CD19-positive cells that is currently being tested in several B-cell leukemia/lymphoma clinical trials. To explore the possibility of using anti-B4-bR in combination with chemotherapy protocols, we investigated the in vitro and in vivo cytotoxic effects of combining it with doxorubicin or etoposide using the lymphoma cell line Namalwa and a P-glycoprotein-expressing cell line, Namalwa/mdr-1, obtained by retroviral infection of Namalwa cells with the mdr-1 gene. Namalwa/mdr-1 cells were slightly more sensitive to anti-B4-bR than Namalwa cells; IC37 values were approximately 4 pmol/L and 8 pmol/L, respectively. When anti-B4-bR was combined simultaneously with doxorubicin or etoposide, additive to supra-additive killing of Namalwa and Namalwa/mdr-1 cells was observed. In xenografts of Namalwa/mdr-1 cells in severe combined immunodeficiency (SCID) mice, doxorubicin and etoposide at their maximum tolerated doses (3 mg/kg x 3 or 15 mg/kg x 3) showed no therapeutic effect. However, treatment with 5 daily bolus injections of anti-B4-bR (50 micrograms/kg) followed by treatment with doxorubicin or etoposide significantly increased the life span of the mice by 129% and 115%, respectively. After treatment with anti-B4-bR, the Namalwa/mdr-1 population expressed lower levels of P-glycoprotein, and this decrease may account for the synergistic action of the drug combinations. These results suggest that anti-B4-bR could be used to good effect in combination with current treatment regimens and further hint at a promising role for this immunotoxin in treatment of disease at the minimal residual disease stage, where cells may be resistant to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Induction of apoptosis by the Bcl-2 homologue Bak.

Cells are eliminated in a variety of physiological settings by apoptosis, a genetically encoded process of cellular suicide. Apoptosis comprises an intrinsic cellular defence against tumorigenesis, which, when suppressed, may contribute to the development of malignancies. The bcl-2 oncogene, which is activated in follicular lymphomas, functions as a potent suppressor of apoptosis under diverse conditions. Here we describe the complementary DNA cloning and functional analysis of a new Bcl-2 homologue, Bak, which promotes cell death and counteracts the protection from apoptosis provided by Bcl-2. Moreover, enforced expression of Bak induces rapid and extensive apoptosis of serum-deprived fibroblasts. This raises the possibility that Bak is directly involved in activating the cell death machinery.

Amino Acid Sequence↗
PubMed1994

A case of hyperemesis gravidarum treated with artificial nutritional support.

A case of severe hyperemesis gravidarum is described in which the parturient required nutritional support. Initially a trial of enteral feeding was attempted but was unsuccessful. Subsequent parenteral nutrition allowed the remainder of the pregnancy to continue and a live infant was delivered by caesarean section at 34 weeks gestation. Criteria for using artificial feeding, the nutritional requirements of a pregnant woman and the potential hazards to the pregnancy by giving artificial nutritional support are reviewed.

Journal Article↗