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Biomedical subjects

J C Donovan

Publications and source records attributed to J C Donovan.

At least 19 recordsLinked to original sources
PubMed2001

Constitutive MEK/MAPK activation leads to p27(Kip1) deregulation and antiestrogen resistance in human breast cancer cells.

Antiestrogens, such as the drug tamoxifen, inhibit breast cancer growth by inducing cell cycle arrest. Antiestrogens require action of the cell cycle inhibitor p27(Kip1) to mediate G1 arrest in estrogen receptor-positive breast cancer cells. We report that constitutive activation of the mitogen-activated protein kinase (MAPK) pathway alters p27 phosphorylation, reduces p27 protein levels, reduces the cdk2 inhibitory activity of the remaining p27, and contributes to antiestrogen resistance. In two antiestrogen-resistant cell lines that showed increased MAPK activation, inhibition of the MAPK kinase (MEK) by addition of U0126 changed p27 phosphorylation and restored p27 inhibitory function and sensitivity to antiestrogens. Using antisense p27 oligonucleotides, we demonstrated that this restoration of antiestrogen-mediated cell cycle arrest required p27 function. These data suggest that oncogene-mediated MAPK activation, frequently observed in human breast cancers, contributes to antiestrogen resistance through p27 deregulation.

Breast Neoplasms↗
PubMed2001

Gene knockout demonstrates that vip3A contributes to the pathogenesis of Bacillus thuringiensis toward Agrotis ipsilon and Spodoptera exigua.

Vip3A is an 89-kDa protein secreted by Bacillus thuringiensis during vegetative growth. To determine the importance of Vip3A for the insect pathogenicity of B. thuringiensis the vip3A gene was deleted from strain HD1, yielding strain HD1Deltavip3A. Compared with HD1, strain HD1Deltavip3A was one-fourth as toxic to Agrotis ipsilon larvae and less than one-tenth as toxic to Spodoptera exigua larvae. When streptomycin was included in the S. exigua diet the toxicity of HD1Deltavip3A was approximately half that of HD1. Addition of HD1 spores increased the toxicity of purified Cry1 protein more than 600-fold against S. exigua, whereas addition of HD1Deltavip3A spores increased toxicity of Cry1 protein approximately 10-fold. These results demonstrate that an important component of B. thuringiensis insecticidal activity against S. exigua is the synthesis of Vip3A protein by B. thuringiensis cells after ingestion of spores and crystal proteins by insect larvae.

Animals↗
PubMed2000

Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells.

Estrogens and antiestrogens influence the G(1) phase of the cell cycle. In MCF-7 breast cancer cells, estrogen stimulated cell cycle progression through loss of the kinase inhibitor proteins (KIPs) p27 and p21 and through G(1) cyclin-dependent kinase (cdk) activation. Treatment with antiestrogen drugs, Tamoxifen or ICI 182780, caused cell cycle arrest, with up-regulation of both p21 and p27 levels, an increase in their binding to cyclin E-cdk2, and kinase inhibition. The requirement for these KIPs in the arrests induced by estradiol depletion or by antiestrogens was investigated with antisense. Antisense inhibition of p21 or p27 expression in estradiol-depleted or antiestrogenarrested MCF-7 led to abrogation of cell cycle arrest, with loss of cyclin E-associated KIPs, activation of cyclin E-cdk2, and S phase entrance. These data demonstrate that depletion of either p21 or p27 can mimic estrogen-stimulated cell cycle activation and indicate that both of these KIPs are critical mediators of the therapeutic effects of antiestrogens in breast cancer.

Base Sequence↗
PubMed1999

Effect of initial nitric oxide concentration on outcome in infants with persistent pulmonary hypertension of the newborn.

A randomized nonblinded comparison of two treatment groups was performed to determine whether treatment of infants with persistent pulmonary hypertension of the newborn using a continuous 6-ppm dose of inhaled nitric oxide (iNO) changes the likelihood of death or utilization of extracorporeal membrane oxygenation (ECMO) when compared to infants treated with 20 ppm iNO for 4 h followed by 6 ppm. Twenty-nine infants with a gestational age >/=34 weeks and a diagnosis of persistent pulmonary hypertension of the newborn were enrolled during the 3- year study period. The relative risk (20/6 vs. 6 ppm) for treatment with ECMO was 3.11 (p = 0.02), for death it was 2.80 (p = 0.32), and for either death or ECMO it was 3.42 (p = 0. 006). There was no apparent advantage of treatment with a higher dosage of iNO at the initiation of therapy in the reduction of death or utilization of ECMO. These data suggest that a continuous lower dose of iNO results in a comparable improvement in oxygenation as a short exposure of higher dose iNO at the initiation of therapy.

Administration, Inhalation↗
PubMed1987

Expression of the mouse P(1)450 gene during differentiation without foreign chemical stimulation.

Transcriptional activation of the P(1)450 and P(3)450 genes, mRNA accumulation, and induction of the P(1)450 and P(3)450 enzymes are known to be stimulated by foreign chemicals such as tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene. It has been established that this induction process is dependent on trans-acting factor(s) that include a complex between the environmental chemical inducer and the aromatic hydrocarbon (Ah) receptor. In this report we show that constitutive P(1)450 mRNA but not P(3)450 mRNA is elevated in 7-day-old mouse embryos and following retinoic acid-induced differentiation of F9 embryonal carcinoma cells. In both instances it is shown that P(1)450 gene activation can occur in the absence of a foreign chemical stimulus. These data suggest that the P(1)450 gene may serve an important developmental function during differentiation.

Animals↗
PubMed1984

Hematological and bone marrow effects of ribavirin in rhesus monkeys.

Ribavirin (Virazole, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a broad-spectrum antiviral compound, was evaluated for effects on blood and bone marrow of rhesus monkeys when administered by intramuscular injection for 10 days in doses of 30 or 100 mg/kg/day (four monkeys/group). Both groups developed a normochromic, normocytic anemia that was mild in the low-dose group and severe in the high-dose group. A dose-related erythroid hypoplasia occurred during the treatment period. Myeloid precursors were not affected. Differential counts of erythroid precursors showed a significant decrease in late erythroid forms while early erythroid forms were either unchanged or increased. Megakaryocyte numbers were increased in both groups. Qualitative changes in marrow cells included vacuolization of erythroid precursors and of occasional white cell precursors and megakaryocytes, and the appearance of bone marrow histiocytes containing red cells in various stages of disintegration. Thrombocytosis occurred in both treatment groups, with platelet counts returning to control values after drug withdrawal. Platelet function was not affected by treatment. No drug-related changes were seen during the treatment period for total and differential leukocyte counts, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. Reticulocyte counts and mean corpuscular volume increased after treatment then returned to control values. Osmotic fragility of erythrocytes was not changed. These data show that in monkey, ribavirin causes a dose-related decrease in circulating red blood cell mass that is due in part to suppression of late erythroid precursors in bone marrow. These effects are reversible when treatment is discontinued and are not predictive of potentially serious or lasting untoward effects of ribavirin.

Animals↗
PubMed1984

Respiration of chemodenervated goats in acute metabolic acidosis.

In awake goats before and after ablation of carotid bodies (CBx) we studied the effect of acute metabolic acidosis (AMA) produced by intravenous infusion of HCl on composition of arterial blood and CSF, and on ventilatory responsiveness to hyperoxic CO2 rebreathing AMA caused decrease in PaCO2 (breathing air at rest) indicating that alveolar ventilation was increased relative to CO2 production; position of CO2 response curves was shifted toward lower values of PCO2. These changes were similar before and after CBx, though the levels of PCO2 in arterial blood during air breathing at rest, and in expired gas at a given level of ventilation during CO2 rebreathing, were higher after CBx. We conclude that a respiratory adaptation to AMA does occur in goats deprived of peripheral chemoreceptors, and is probably mediated by the central chemoreceptors.

Acidosis↗
PubMed1984

Morphological alterations in blood and bone marrow of ribavirin-treated monkeys.

The antiviral drug ribavirin (1, beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) produced significant hematologic effects when administered to rhesus monkeys by intramuscular injection over 10 days in doses of 30 or 100 mg/kg/day. The monkeys developed dose-related progressive anemia and thrombocytosis associated with marrow erythroid hypoplasia and megakaryocyte hyperplasia. In addition, bone marrow examination revealed phagocytosis of erythroid elements by histiocytes; vacuolization of erythroid precursors, and to a lesser extent precursors of other cell types; and occasional erythroid precursors with megaloblastoid appearance. The alterations were transient and disappeared on discontinuation of the drug.

Animals↗
PubMed1983

Acclimatization to high altitude in goats with ablated carotid bodies.

In awake goats with ablated carotid bodies, we studied resting pulmonary ventilation, CO2 production, composition of arterial blood and cerebrospinal fluid (CSF), and ventilatory responsiveness to hyperoxic CO2 rebreathing at sea level (SL) and after 3 days at simulated high altitude (HA) (PB 446 +/- 5 Torr, equivalent to 4,300 m). At HA, resting pulmonary ventilation was increased, resulting in marked hypocapnia with appropriate base deficit in blood plasma; CSF became more alkaline; CO2-response curves were shifted to lower PCO2 levels, and their slopes were steeper than at SL. Although these changes in regulation of respiration were not demonstrably different from those seen after normal acclimatization to HA with carotid bodies intact, the mechanisms of their initiation and development are probably different.

Acclimatization↗
PubMed1983

Acute clinical malaria (Plasmodium inui) in a cynomolgus monkey (Macaca fascicularis).

Acute clinical malaria caused by Plasmodium inui was diagnosed in an adult female cynomolgus monkey (Macaca fascicularis) 4 years after importation into the United States. Stress and immunosuppression associated with experimentation completed 2 weeks earlier may have contributed to the development of severe clinical disease. Clinical findings included severe regenerative anemia, hepatosplenomegaly, weakness, lethargy, weight loss, and anorexia. The infection was treated and successfully eliminated with chloroquine hydrochloride administered intramuscularly at a dose of 5 mg/kg base given at 0, 6, 24, 48, and 72 hours. Treatment also included a blood transfusion and intensive supportive care.

Acute Disease↗
PubMed1983

Hematologic characterization of naturally occurring malaria (Plasmodium inui) in cynomolgus monkeys (Macaca fascicularis).

Twenty of 47 recently imported cynomolgus monkeys (Macaca fascicularis) were found to have malarial infections. The agent identified was Plasmodium inui. All infections were subclinical in nature. Parasitemias ranged from 10 to 900 parasites/mm3 of whole blood. Pre- and post-treatment hematologic values were evaluated following treatment with chloroquine. Treatment was effective in clearing parasitemias from 13 of 14 infected monkeys. Pretreatment values of hematocrit, hemoglobin, and mean corpuscular volume were significantly different in infected animals compared to noninfected animals. While post-treatment hemoglobin and hematocrit values returned to noninfected control levels, mean corpuscular volume values of infected animals remained significantly lower in the post-treatment period.

Animals↗
PubMed1982

Results of bunion correction using Mitchell osteotomy.

The results of Mitchell osteotomy for repair of hallux valgus/bunion deformity are presented. Twenty-five consecutive patients on whom 33 first metatarsal osteotomy/bunionectomy procedures of the Mitchell-Hawkins variety demonstrate satisfactory and durable reduction of deformity. These was an average decrease in the first intermetatarsal angle of 6.1 degrees and an average decrease in the hallux abductus angle of 18.4 degrees. This procedure successfully corrects an elevated intermetatarsal angle and an elevated proximal articular set angle at a single osteotomy site. Nonunion of the osteotomy site was not found. The most common complication (9%) was second metatarsalgia. This was found in one patient with a pre-existing callus, and two patients due to technical error.

Hallux Valgus↗
PubMed1977

An independent study program within a medical curriculum.

The Independent Study Program (ISP) at the University of Rochester School of Medicine and Dentistry is described and its objectives are specified. Experimental (ISP) students and two matched (non-ISP students from the same class) groups were studied in two successive second-year medical school classes. Data were gathered only post-ISP for the first class and both pre- and post-ISP for the second. The data included measures of achievement, personality characteristics, and academic-professional experience. Experimental and control groups were not significantly different on achievement and academic-professional measures but did differ on certain measures of personality and values. The groups also differed on their evaluations of curriculum and reports of study habits. Fache ISP program was considered, and it was found that the ISP is less expensive of faculty time than is the regular curriculum but involves higher nonfaculty costs.

Achievement↗