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At least 487 records · Page 27Linked to original sources
PubMed1995

Role of metabolism by esterase and cytochrome P-450 in cocaine-induced suppression of the antibody response.

To investigate the role of metabolism in cocaine-induced immunosuppression, diazinon and beta-ionone were administered as an esterase inhibitor and a cytochrome P-450 (P-450) inducer, respectively, to B6C3F1 female mice. When 10 or 30 mg/kg of diazinon was administered 30 min before cocaine (30 mg/kg) was administered i.p. for 7 consecutive days, the suppression of the T-dependent antibody response to sheep red blood cells was potentiated greatly when compared to the suppression by cocaine alone. Spleen and thymus weights were decreased significantly and serum glutamate-pyruvate transaminase activities were elevated dramatically when cocaine and diazinon were administered together. beta-Ionone was administered s.c. for 7 consecutive days and the P-450 activities were determined 3 days after the last administration. beta-Ionone induced cocaine N-demethylation, which is the first step in the activation of cocaine to the metabolites capable of producing hepatotoxicity, as well as P-450IA1- and P-450IIB1-specific monooxygenases. The inductive effects of beta-ionone on P-450IA1/2 and P-450IIB1/2 proteins were confirmed by using Western immunoblotting with selective monoclonal antibodies. In addition, when beta-ionone (600 mg/kg) was administered with cocaine for 7 days, the suppression of the antibody response was potentiated greatly, thymus weight was decreased significantly and serum glutamate-pyruvate transaminase was elevated. Our present results suggest that inhibition of the esterase pathway of cocaine shunts the metabolism of cocaine into an immunotoxic pathway, and that the metabolism of cocaine by P-450 may be the critical pathway for the generation of the metabolites capable of suppressing the antibody response.

Animals↗
PubMed2003

Immunosuppression in Pediatric Heart Transplantation: 2003 and Beyond.

Advances in immunosuppressive therapy have contributed to the improved long-term survival of pediatric heart transplant recipients over the past two decades. The introduction of cyclosporine in the early 1980s (the first oral agent to selectively target T-lymphocyte pathways) led to a dramatic reduction in acute rejection rates and improved graft and patient survival. A combination of cyclosporine, azathioprine, and corticosteroids ("triple therapy") became the standard of care for pediatric and adult heart transplantation. The introduction of several new agents in the past decade has resulted in an almost infinite number of potential immunosuppressive regimens, none of which have been (or are likely to be) tested in randomized clinical trials in children. Tacrolimus is replacing cyclosporine as the primary calcineurin inhibitor in many programs. Mycophenolate mofetil, despite its increased cost, is likely to replace azathioprine as the adjunctive antimetabolite of choice in heart transplantation. Furthermore, target of rapamycin inhibitors, such as sirolimus, will likely be used in lieu of antimetabolite agents if their known myointimal antiproliferative effects are demonstrated to reduce or prevent graft vasculopathy (chronic rejection) in humans. With the availability of more potent immunosuppressive agents, early steroid withdrawal or complete steroid avoidance will become the standard of care in most pediatric transplant programs. Complete avoidance of steroids can be facilitated by the use of induction therapy with polyclonal anti-T-cell antibodies (eg, rabbit antithymocyte globulin ) or with the use of nondepleting antibodies that block the interleukin-2 receptor (eg, basiliximab, daclizumab). All these agents appear to have a good safety profile and are likely to lead to a resurgence of interest in induction therapy as a strategy to avoid chronic use of corticosteroids in children. As the elucidation of immunosuppressive pathways continues to advance, many newer immunosuppressive agents will be developed that target specific critical pathways in the immune response to the allograft. These advances should lead to more focused immunosuppression, greater drug synergism, reduction in the doses of individual agents, steroid-sparing regimens, and reduction in end-organ toxicities. The ultimate goal will be to define a perioperative therapeutic regimen that will result in a state of " transplantation tolerance," in which the patient will indefinitely accept their allograft without the need for chronic immunosuppressive therapy.

Journal Article↗
PubMedDate not supplied

[Liquid radioactive waste in health activities: annual dosage to the population].

A survey was taken of the amount of radionuclides, acquired, utilized, and released in one year's time, in the Adige river by the USL (Local Division of the National Public Health System) of Verona. The critical pathways of environmental pollution were analyzed and the individual and collective doses of some critical population groups and the population as a whole were compiled. Some suggestions to reduce the collective doses both from radioactive releases and diagnostic use of radionuclides are given.

Body Burden↗
PubMed2004

Chlamydomonas reinhardtii in the landscape of pigments.

This review focuses on the biosynthesis of pigments in the unicellular alga Chlamydomonas reinhardtii and their physiological and regulatory functions in the context of information gathered from studies of other photosynthetic organisms. C. reinhardtii is serving as an important model organism for studies of photosynthesis and the pigments associated with the photosynthetic apparatus. Despite extensive information pertaining to the biosynthetic pathways critical for making chlorophylls and carotenoids, we are just beginning to understand the control of these pathways, the coordination between pigment and apoprotein synthesis, and the interactions between the activities of these pathways and those for other important cellular metabolites branching from these pathways. Other exciting areas relating to pigment function are also emerging: the role of intermediates of pigment biosynthesis as messengers that coordinate metabolism in the chloroplast with nuclear gene activity, and the identification of photoreceptors and their participation in critical cellular processes including phototaxis, gametogenesis, and the biogenesis of the photosynthetic machinery. These areas of research have become especially attractive for intensive development with the application of potent molecular and genomic tools currently being applied to studies of C. reinhardtii.

Animals↗
PubMed1996

Signal transduction mechanisms in the ischemic and reperfused myocardium.

The cellular mechanisms regulating myocardial dysfunction during ischemia and subsequent reperfusion are complex. As can be determined from this review, it is clear that signal transduction pathways are altered during these conditions, which may explain, in part, the pathophysiology of ischemia and reperfusion. With respect to beta-adrenoceptor signal transduction, adaptive changes during ischemia and reperfusion ensure that this critical pathway for the regulation of cardiac function remains intact. Additionally, although the relative contribution of alpha 1-adrenoceptors to the regulation of cardiac function is minimal in normal myocardium, these receptors clearly exacerbate conditions associated with the generation of arrhythmias during reperfusion. It is likely that this enhancement of arrhythmogenesis is related to the activation of NHE by a PKC-dependent mechanisms. The importance of non-receptor-mediated signal transduction as a mediator of ischemia and reperfusion injury has long been established with respect to products of membrane lipid breakdown. As discussed, recent evidence now suggests that other compounds formed during ischemia and reperfusion, such as reactive oxygen species and NO, are also linked to cellular second messenger systems. In conclusion, as signal transduction is critical for normal myocardial function, signal transduction pathways are of even more importance during ischemia and reperfusion. There is an increasing interest in the role of non-receptor-mediated signal transduction as a mediator of ischemia and reperfusion injury and it is hoped that these pathways may represent new levels for therapeutic intervention.

Animals↗
PubMed2004

Monoclonal antibodies in the treatment of colorectal cancer.

Monoclonal antibodies have been developed to target specific proteins involved in the development and progression of cancer. These reagents have the advantage of exquiste specificity, and as currently engineered, low toxicity. The impact monoclonal antibody therapy has recently been demonstrated in colorectal cancer, in which two pathways critical to carcinogenesis have been targeted. The targets are the epidermal growth factor receptor signaling pathway and angiogenesis. Antibodies directed to proteins in both pathways have shown significant activity especially in combination with chemotherapy, and studies in the adjuvant setting are in progress. We review the use of monoclonal antibodies in the treatment of colorectal cancer with particular attention to edrecolomab (Mab 17-1A), bevacizumab (Avastin), cetuximab (IMC-C225), ABX-EGF and EMD 72000. Additional compounds are in earlier stages of development, and the future of this approach in solid tumours is promising.

Antibodies, Monoclonal↗
PubMed2005

The negative regulation of phosphoinositide 3-kinase signaling by p85 and it's implication in cancer.

The phosphoinositide 3-kinase (PI3K) signaling pathway critically regulates cell growth and cell survival. Mutations that lead to aberrant activation of this pathway are frequent events in human cancers. Here we discuss some recent studies identifying the mechanisms by which p85, the regulatory subunit of PI3K, negatively regulates PI3K signaling. While necessary for the stability and membrane recruitment of the p110 catalytic subunit of PI3K. p85 represses the basal activity of p110 in the absence of growth factor stimulation. In its unbound, free form, p85 sequesters the adaptor protein IRS-1 and therefore limits the extent of PI3K signaling downstream of the insulin and IGF-1 receptors. These findings lend new insight to how changes in p85 gene dosage or mutations in p85 could lead to the hyper-activation of PI3K and thus contribute towards tumorigenesis.

Animals↗
PubMed2006

Recent developments in colorectal cancer treatment by monoclonal antibodies.

A growing understanding of the molecular mechanisms involved in cancer biology and continuous refinement of available technologies for drug discovery have prompted the development of new therapeutic tools targeting specific cancer-associated molecular pathways. Among these so-called biological therapies, monoclonal antibodies have now reached the time of clinical application. Besides initial development of the murine antibody edrecolomab, the impact of monoclonal antibodies on cancer therapy has recently been clearly demonstrated in colorectal cancer by targeting two major pathways critical to tumourigenesis: the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signalling pathways. These antibodies showed significant clinical activity in advanced colorectal cancer, especially when combined with chemotherapy. This paper reviews the status of the monoclonal chimeric antibody cetuximab (Erbitux) and other anti-EGFR antibodies, and of bevacizumab (Avastin; an anti-VEGF humanised monoclonal antibody), in colorectal cancer treatment.

Animals↗
PubMed2004

Rice octadecanoid pathway.

Plant jasmonic acid (JA) and structurally similar animal prostaglandins play pivotal roles in regulating cellular responses against environmental cues, including the innate immune response(s). In plants, JA and its immediate precursor 12-oxo-phytodienoic acid (OPDA) are synthesized by the octadecanoid pathway, which employs at least five enzymes (lipase, lipoxygenase, allene oxide synthase and cyclase, and OPDA reductase), in addition to the enzymes involved in the beta-oxidation steps. Genetic, molecular, and biochemical analyses have led to the identification of almost all the genes of the octadecanoid pathway in Arabidopsis--a model dicotyledonous plant. In this regard, rice (Oryza sativa L.)--an important socio-economic monocotyledonous model research plant--remains poorly characterized. Until now, no gene has been specifically associated with this pathway. It is therefore of utmost importance to identify, characterize, and assign the pathway specific genes in rice. In this review, we have surveyed the rice genome, extracted a large number of putative genes of the octadecanoid pathway, and discussed their relationship with the known pathway genes from other plant species. Moreover, the achievements made so far on the rice octadecanoid pathway have also been summarized to reflect the contribution of rice towards extending our knowledge on this critical pathway in plants.

Animals↗
PubMed2004

Ras/MEK pathway is required for NGF-induced expression of tyrosine hydroxylase gene.

Neurotrophins are essential for the development and survival of catecholaminergic neurons. However, the critical pathway for expression of the tyrosine hydroxylase (TH) gene induced by neurotrophin is still unclear. Here we found that Ras/MEK pathway is required for NGF-induced expression of the TH gene in PC12D cells. Induction of TH mRNA by NGF was abolished by pretreatment of the cells with U0126, an inhibitor for MEK1/2, but not with inhibitors for p38 MAPK, PI3K, and PKA. U0126 inhibited TH promoter activity at the same concentration as it acted on ERK1/2 phosphorylation. A dominant-negative form of Ras suppressed the NGF-induced activation of the TH reporter gene, and transient transfection of cells with wild-type Ras and an active form of MEK1 increased the TH promoter activity. The reporter assay also demonstrated that the Ras/MEK pathway acted on both the AP-1-binding motif and the cAMP-responsive element in the TH promoter.

Amino Acid Motifs↗
PubMed1994

The synergy of pathways and algorithms: two tools work better than one.

BACKGROUND: Clinical quality improvement efforts at the Medical Center Hospital of Vermont (MCHV) led to the development of critical pathways, which show the ideal plan of care, and algorithms, which help clinicians make one of many complicated decisions within a plan of care. A synergy appears to develop when pathways and algorithms are used together. DEVELOPMENT OF PATHWAYS AND ALGORITHMS: A steering committee supports and oversees pathway and algorithm efforts. A quarterly tracking report updating progress for all pathways and algorithms is circulated to all nurse managers, medical staff, and administrators. When combining pathways and algorithms, the pathway is created first. Algorithms are developed for trouble spots within a pathway. CORONARY ARTERY BYPASS GRAFT (CABG) PATIENTS: Having developed the pathway for CABG patients, the CABG case management team meets monthly to review outcomes and variances. For example, an algorithm for managing atrial arrhythmias--the chief cause of variance for one month's results--was developed. The combination of pathways and algorithms for CABG patients has resulted in a reduction of 2.5 days for total length of stay (including 1 day on the surgical intensive care unit [SICU]), for a mean cost savings of $3,500. Re-admission to the SICU, reintubation, and mortality rates have all decreased. CONCLUSION: The idea of reaping the benefits of both pathways and algorithms is becoming more popular at MCHV, where teams use algorithms to improve on complicated processes underlying the pathways.

Algorithms↗
PubMed2015

NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability.

NUCKS1 (nuclear casein kinase and cyclin-dependent kinase substrate 1) is a 27 kD chromosomal, vertebrate-specific protein, for which limited functional data exist. Here, we demonstrate that NUCKS1 shares extensive sequence homology with RAD51AP1 (RAD51 associated protein 1), suggesting that these two proteins are paralogs. Similar to the phenotypic effects of RAD51AP1 knockdown, we find that depletion of NUCKS1 in human cells impairs DNA repair by homologous recombination (HR) and chromosome stability. Depletion of NUCKS1 also results in greatly increased cellular sensitivity to mitomycin C (MMC), and in increased levels of spontaneous and MMC-induced chromatid breaks. NUCKS1 is critical to maintaining wild type HR capacity, and, as observed for a number of proteins involved in the HR pathway, functional loss of NUCKS1 leads to a slow down in DNA replication fork progression with a concomitant increase in the utilization of new replication origins. Interestingly, recombinant NUCKS1 shares the same DNA binding preference as RAD51AP1, but binds to DNA with reduced affinity when compared to RAD51AP1. Our results show that NUCKS1 is a chromatin-associated protein with a role in the DNA damage response and in HR, a DNA repair pathway critical for tumor suppression.

Cell Line↗
PubMed2002

Cutting edge: identification of c-Rel-dependent and -independent pathways of IL-12 production during infectious and inflammatory stimuli.

The production of IL-12 is required for immunity to many intracellular pathogens. Recent studies have shown that c-Rel, a member of the NF-kappaB family of transcription factors, is essential for LPS-induced IL-12p40 production by macrophages. In this study, we demonstrate that c-Rel is also required for IL-12p40 production by macrophages in response to Corynebacterium parvum, CpG oligodeoxynucleotides, anti-CD40 and low molecular weight hyaluronic acid. However, c-Rel(-/-) mice infected with Toxoplasma gondii produce comparable amounts of IL-12p40 to infected wild-type mice and have an IL-12-dependent mechanism of resistance to this infection. Furthermore, c-Rel was not required for IL-12p40 production by macrophages or dendritic cells in response to soluble Toxoplasma Ag, and neutrophils from c-Rel(-/-) mice contain normal amounts of preformed IL-12p40. Together these studies reveal the presence of c-Rel-dependent pathways critical for IL-12p40 production in response to inflammatory stimuli and demonstrate a novel c-Rel-independent pathway of IL-12p40 production during toxoplasmosis.

Animals↗
PubMedDate not supplied

Home care of the prostate cryosurgery patient.

1. Through the use of the pathway process, variation in home care of the prostate cryosurgery patient is reduced in caregiver technique and efficiency of care delivery is improved. More importantly, patient outcomes are closely monitored and multidisciplinary continuity of care is promoted. The pathway helps ensure that appropriate resources are initiated and used in appropriate timeframes. 2. A patient version of the critical pathway, written in lay terminology, is given to patients to define their responsibilities in the care process. This method encourages patient participation in care. 3. The purpose of home care is to educate the patient about his disease process and treatment regimen, and encourage him to participate in his treatment and recovery. The prostatic cryosurgery pathway gives him an opportunity to be active in his care.

Cryosurgery↗
PubMed2005

Metastases and their microenvironments: linking pathogenesis and therapy.

The pathogenesis of metastasis depends on multiple favorable interactions of tumor cells with host homeostatic mechanisms. Interruption of one or more of these interactions can lead to the inhibition or eradication of cancer metastases. For many years, all efforts to treat cancer concentrated on the inhibition of growth or the destruction of tumor cells. A strategy of both eradication of tumor cells (e.g. by chemotherapy and immunotherapy) and modulation of the host microenvironment (e.g. tumor vasculature and hypoxia) is an additional, relatively novel approach to cancer treatment. Recent advances in our understanding of the biological basis of cancer metastasis open up unprecedented opportunities for translating basic research to clinical treatment of cancer. This research includes the unraveling of the genetic make-up of tumors and genome-wide expression analyses, thereby identifying many potential targets for therapy. Drugs acting on tumor cells which have a metastasis-prone mutational or expression status (by classical or targeted chemotherapy) as well as drugs affecting host-mediated survival pathways must be combined in order to create therapeutic synergy. Therapeutic maneuvers may target receptor tyrosine kinases (EGFR, VEGFR, FGFR), chemokines or G-protein-coupled receptors (CXCR4, CXCR2, EphB2), hypoxia-inducible factor (HIF), and signaling pathways (c-Src, PI3K, Akt, chaperon complexes) in tumor cells. Moreover, stromal and immunological cells and their cytokines coordinate critical pathways that exert important roles in the ability of tumors to invade and metastasize, thus suppressive cytokines (IL-6 and IL-10) and neutralizing specific antibodies might subvert conditions for metastasis.

Animals↗
PubMed2004

The Akt pathway: molecular targets for anti-cancer drug development.

The serine/threonine kinase Akt functions intracellularly as a cardinal nodal point for a constellation of converging upstream signaling pathways, which involve stimulation of receptor tyrosine kinases such as IGF-1R, HER2/Neu, VEGF-R, PDGF-R), and an assembly of membrane-localized complexes of receptor-PI-3K and activation of Akt through the second messenger PIP(3). The integration of these intracellular signals at the level of Akt and its kinase activity, regulates the phosphorylation of its several downstream effectors, such as NF-kappa B, mTOR, Forkhead, Bad, GSK-3 and MDM-2. These phosphorylation events in turn mediate the effects of Akt on cell growth, proliferation, protection from pro-apoptotic stimuli, and stimulation of neo-angiogenesis. Because Akt and its upstream regulators are deregulated in a wide range of solid tumors and hematologic malignancies, and in view of the aforementioned biologic sequelae of this pathway, the Akt pathway is considered a key determinant of biologic aggressiveness of these tumors, and a major potential target for novel anti-cancer therapies. This review focuses on ongoing translational efforts to therapeutically target Akt and its biologic sequelae, either at the level of Akt itself or at the levels of its upstream regulators and downstream effectors. Because Akt is also important for proliferative and anti-apoptotic signaling pathways critical for normal cells, particular emphasis is placed on the fine-tuning the targeting of individual components of this pathway to maximize the therapeutic index of anti-cancer strategies based on the PI-3K/Akt pathway.

Animals↗
PubMedDate not supplied

[Radioactive waste monitored around the city hospitals in Brescia. Results of a radiometric survey and model of the radiologic impact on the environment].

The release into environment of liquid radioactive wastes coming from the metabolic therapy department of the Spedali Civili in Brescia was monitored during six months, with a rate of release of about 20 divided by 50 mCi of 131I every 30 divided by 40 days. Samples of 10 liters of liquid, taken from sewers downstream from the release point during a release operation, was percolated on 50 cm3 of ionic exchange resin in order to achieve a suitable counting rate with a Ge(Li) crystal spectrometer, connected to a 2048 channel analyzer. From these measurements a dilution curve along the sewers course was obtained, allowing one to know, for a given radioiodine concentration at the release point, concentration at every point downstream. In this way, by means of a simple linear compartmental model, it is possible to calculate the average individual dose taken by individuals who are living in the region (250.000 inhabitants) in one year of release operations. In our case we considered, as critical pathways to man, cow milk, meat, cereals and fruits: we obtained for thyroid, which in the case of radioiodine is the critical organ, an individual annual dose of 5,41 x 10(-4) mrem, while for total body we obtained 9,49 x 10(-7) mrem.

Environmental Pollution↗
PubMed1995

Extending the application of critical path methods.

Most health care organizations are using critical pathways in an attempt to reduce the variation in patient care, improve quality, enhance communication, and reduce costs. Virtually all of the critical path efforts to date have developed tables of treatments, medications, and so forth by day and have displayed them in a format known as a Gantt chart. This article presents a methodology for identifying the true "time-limiting" critical path, describes three additional methods for presenting the information--the network, precedent, and resource formats--and shows how these can significantly enhance current critical path efforts.

Academic Medical Centers↗