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Biomedical subjects

D Joyce

Publications and source records attributed to D Joyce.

At least 19 recordsLinked to original sources
PubMed2001

NF-kappaB and cell-cycle regulation: the cyclin connection.

The cyclins are a family of proteins that are centrally involved in cell cycle regulation and which are structurally identified by conserved "cyclin box" regions. They are regulatory subunits of holoenzyme cyclin-dependent kinase (CDK) complexes controlling progression through cell cycle checkpoints by phosphorylating and inactivating target substrates. CDK activity is controlled by cyclin abundance and subcellular location and by the activity of two families of inhibitors, the cyclin-dependent kinase inhibitors (CKI). Many hormones and growth factors influence cell growth through signal transduction pathways that modify the activity of the cyclins. Dysregulated cyclin activity in transformed cells contributes to accelerated cell cycle progression and may arise because of dysregulated activity in pathways that control the abundance of a cyclin or because of loss-of-function mutations in inhibitory proteins.Analysis of transformed cells and cells undergoing mitogen-stimulated growth implicate proteins of the NF-kappaB family in cell cycle regulation, through actions on the CDK/CKI system. The mammalian members of this family are Rel-A (p65), NF-kappaB(1) (p50; p105), NF-kappaB(2) (p52; p100), c-Rel and Rel-B. These proteins are structurally identified by an amino-terminal region of about 300 amino acids, known as the Rel-homology domain. They exist in cytoplasmic complexes with inhibitory proteins of the IkappaB family, and translocate to the nucleus to act as transcription factors when activated. NF-kappaB pathway activation occurs during transformation induced by a number of classical oncogenes, including Bcr/Abl, Ras and Rac, and is necessary for full transforming potential. The avian viral oncogene, v-Rel is an NF-kappaB protein. The best explored link between NF-kappaB activation and cell cycle progression involves cyclin D(1), a cyclin which is expressed relatively early in the cell cycle and which is crucial to commitment to DNA synthesis. This review examines the interactions between NF-kappaB signaling and the CDK/CKI system in cell cycle progression in normal and transformed cells. The growth-promoting actions of NF-kappaB factors are accompanied, in some instances, by inhibition of cellular differentiation and by inhibition of programmed cell death, which involve related response pathways and which contribute to the overall increase in mass of undifferentiated tissue.

Animals↗
PubMed2001

Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis.

OBJECTIVE: To review the mechanisms of action and rationale for the use of recombinant human activated protein C in the treatment of severe sepsis. Specifically, we focus on the mechanisms of action in the protein C pathway that converge to modulate the pathophysiology of severe inflammatory disease and sepsis. This analysis includes a discussion of the role of activated protein C in directly modulating cell system biology, independent of antithrombotic activity. DATA SOURCES/STUDY SELECTION: Published research and review articles relating to the protein C pathway, recombinant human protein C, and the role of protein C in sepsis. Data were also derived from broad gene profiling in model systems of endothelial dysfunction. DATA EXTRACTION AND SYNTHESIS: Relevant studies were included to support discussion of the unique mechanistic aspect of protein C and its role in the pathogenesis of severe sepsis. We discuss the potential of activated protein C as a unique system modulator for the treatment of severe sepsis and other systemic inflammatory responses that result in microvascular coagulopathy, endothelial dysfunction, and vascular bed failure. CONCLUSIONS: The protein C pathway plays a unique role in modulating vascular function. As an antithrombotic/profibrinolytic agent, it plays a clear role in maintaining vascular patency. Moreover, it has anti-inflammatory properties and appears to play a unique role as an antiapoptotic and endothelial cell survival factor. In states of systemic inflammatory activation, loss of protein C due to consumptive processes results in a compromised ability to modulate coagulation as well as inflammatory and cell survival functions. This compromise leads to vascular dysfunction, end-organ failure, and death. Replacement with recombinant human activated protein C offers a system-modulating approach to improved outcome.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Reversed effects of RU486 and anisomycin on memory retention of light exposure or corticosterone facilitation in the dark-incubated chicks.

Memory formation for a weak passive avoidance task in the dark-incubated chicks is facilitated by light exposure or corticosterone administration at optimally pre-hatch time points. To explore the potential mechanisms underlying activation of brain memory function development by light or corticosterone exposure during late embryo, steroid receptor antagonist RU486, or protein synthetic inhibitor anisomycin, was administered intraembryonically to the embryos of either only 24-h light-exposure or complete dark-hatched on embryonic day 20 (E20). The results showed that RU486 and anisomycin significantly retarded the facilitated retention both by light and corticosterone exposure in the dark-incubated chicks. They also suggest that the act of corticosterone or light exposure on the development of brain memory function is mediated by the effect of steroid receptor, or afterward on related protein syntheses that is involved in memory formation of post-hatched performance of day-old chicks.

Animals↗
PubMed2001

Rho family GTPases regulate mammary epithelium cell growth and metastasis through distinguishable pathways.

BACKGROUND: Relatively few genes have been shown to directly affect the metastatic phenotype of breast cancer epithelial cells in vivo. The Rho family of proteins, incluing the Rho, Rac and Cdc42 subfamilies, are related to the small GTP binding protein Ras and regulated diverse biological processes including gene transcription, cytoskeletal organization, cell proliferation and transformation. The effects of Cdc42, Rac and Rho on the actin cytoskeleton suggested a possible role for Rho proteins in cellular motility and metastasis; however, a formal analysis of the role of Rho proteins in breast cancer cellular growth and metastasis in vivo had not previously been performed. MATERIALS AND METHODS: We generated a panel of MTLn3 rat mammary adenocarcinoma cells that expressed similar levels of dominant inhibitory mutants of Cdc42-, Rac- and Rho-dependent signaling, to examine the contribution of these GTPases to cell spreading, guided chemotaxis, and metastasis in vivo. The ability of Rho proteins to regulate intravasation into the peripheral blood was determined by implanting MTLn3 cell stable dominant negative lines in nude mice and measuring the formation of breast cancer cell colonies grown from the peripheral blood. Serial sectioning of the lungs was performed to determine the presence of metastasis in mice in which mammary tumors expressing the dominant negative Rho family proteins had grown to a similar size. RESULTS: Cell spreading of MTLn3 cells was selectively abrogated by N17Rac1. N19RhoA and N17Cdc42 reduced the number of focal contacts (FCs) and disrupted the co-localization of vinculin with phosphotyrosine at FCs. While N17Rac1 and N17Cdc42 preferentially inhibited colony formation in soft agar, all three GTPases affected cell growth in vivo. To distinguish effects on tumorigenicity from intravasation into the bloodstream, implanted tumors were grown to the same size in nude mice. Each dominant inhibitory Rho protein reduced intravasation into the peripheral blood. Lung metastasis of MTLn3 cells was also abrogated by the dominant inhibitory Rho proteins, despite the presence of residual CFU. CONCLUSIONS: These studies demonstrate for the first time a critical role for the Rho GTPases involving independent signaling pathways to limit mammary tumor cellular growth and metastasis in vivo.

Adenocarcinoma↗
PubMed2000

Pharmacokinetics of ropivacaine following caudal analgesia in children.

Ropivacaine has a favourable toxicity profile for epidural anaesthesia in adults, so it may also be an appropriate agent for epidural analgesia in children. We therefore designed this study to determine the pharmacokinetic variables of ropivacaine relevant to the risk of toxicity, after caudal administration in children. We studied nine healthy children, aged 1-6 years who received 1 ml.kg-1 of ropivacaine 0.25% for caudal analgesia. Venous blood samples were collected at intervals for 12 h after injection. Total plasma concentration of ropivacaine was assayed by high performance liquid chromatography, and pharmacokinetic descriptors were estimated from the plasma concentration-time data. The median peak venous plasma concentration was 799 microg.l-1 [interquartile range (IQR) 707-1044 microg.l-1], and was reached at a median time of 1.5 h (IQR 0.5-2 h). The mean elimination half-life was 3.9 h (95% CI 2.7-5.0 h), and the mean apparent clearance and volume of distribution were 7.6+/-1. 6 ml.min-1.kg-1 (95% CI 6.1-9.1 ml.min-1.kg-1) and 2.4+/-0.6 l.kg-1 (95% CI 1.9-3.0 l.kg-1), respectively. Analgesia was satisfactory in all cases and no systemic ropivacaine toxicity was observed. Caudal administration of weight-adjusted doses of ropivacaine to children resulted in systemic exposure similar to that reported for adults. No systemic toxicity was observed. The findings strengthen predictions that the relative systemic safety of epidural ropivacaine in adults will apply to children. However, the pharmacokinetics and safety of epidural ropivacaine need to be studied further in children with circumstances that affect drug disposition and systemic tolerance.

Adult↗
PubMed1999

Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-kappaB-dependent pathway.

The small GTP-binding protein Rac1, a member of the Ras superfamily, plays a fundamental role in cytoskeleton reorganization, cellular transformation, the induction of DNA synthesis, and superoxide production. Cyclin D1 abundance is rate-limiting in normal G(1) phase progression, and the abundance of cyclin D1 is induced by activating mutations of both Ras and Rac1. Nuclear factor-kappaB (NF-kappaB) proteins consist of cytoplasmic hetero- or homodimeric Rel-related proteins complexed to a member of the IkappaB family of inhibitor proteins. In the current studies, activating mutants of Rac1 (Rac(Leu-61), Rac(Val-12)) induced cyclin D1 expression and the cyclin D1 promoter in NIH 3T3 cells. Induction of cyclin D1 by Rac1 required both an NF-kappaB and an ATF-2 binding site. Inhibiting NF-kappaB by overexpression of an NF-kappaB trans-dominant inhibitor (nonphosphorylatable IkappaBalpha) reduced cyclin D1 promoter activation by the Rac1 mutants, placing NF-kappaB in a pathway of Rac1 activation of cyclin D1. Specific amino acid mutations in the amino-terminal effector domain of Rac(Leu-61) had comparable effects on NF-kappaB transcriptional activity and activation of the cyclin D1 promoter. The NF-kappaB factors Rel A (p65) and NF-kappaB(1) (p50) induced the cyclin D1 promoter, requiring both the NF-kappaB binding site and the ATF-2 site. Stable overexpression of Rac(Leu-61) increased binding of Rel A and NF-kappaB(1) to the cyclin D1 promoter NF-kappaB site. Activation of Rac1 in NIH 3T3 cells induces both NF-kappaB binding and activity and enhances expression of cyclin D1 through an NF-kappaB and ATF-2 site in the proximal promoter, suggesting a critical role for NF-kappaB in cell cycle regulation through cyclin D1 and Rac1.

3T3 Cells↗
PubMed1995

Rates of tibial osteotomies in Canada and the United States.

This study determined the temporal trends and factors associated with the rates of performance of tibial osteotomies from 1985 to 1990 in Ontario, Canada and the United States. The Health Care Financing Administration, Ontario Health Insurance Plan, and National Hospital Discharge Survey databases were used to determine the number of osteotomies from 1985 to 1990. Osteotomy rates decreased in both countries approximately by 11% to 14% per year in patients 65 years and older and by 3% to 4% per year in patients younger than 65 years. Men received twice as many osteotomies as women in both countries. In the United States, the average rate of tibial osteotomies was 2 to 3 times lower than in Ontario.

Age Factors↗