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Results for “Gatekeeping”

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At least 271 records · Page 15Linked to original sources
PubMed2006

Mechanisms of disease: Ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors.

Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease. Several inhibitors of insulin signaling have a role in human insulin resistance. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its beta-subunit autophosphorylation. E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. Genetic studies also support a primary role of E-NPP1 in insulin resistance. Among other variants, a missense polymorphism, Lys121Gln, has been described. The Gln121 variant is a stronger inhibitor than Lys121 of insulin receptor function, and is associated with insulin resistance, type 2 diabetes and both cardiovascular and nephrovascular complications in diabetic patients. E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. Understanding the mechanisms that regulate E-NPP1 expression and/or function might render this protein a new target for strategies to treat and prevent type 2 diabetes and cardiovascular disease.

Animals↗
PubMed1998

The gatekeepers.

Explore the source record for details and available documents.

Crystallography↗
PubMed2005

Gatekeeper pathways and cellular background in the pathogenesis and therapy of AML.

Acute myelogenous leukemia (AML) is characterized by the accumulation of immature cells due to disturbed differentiation and proliferation of the myeloid lineage. Genetic alterations affecting transcription factors and receptor tyrosine kinases have been identified in AML and causally linked to the disease. The goal of this review is to address the role of the different genetic alterations in self-renewal and proliferation and to discuss the cellular background in which these events occur during the pathogenesis of AML. Data from AML samples, clinical studies and mouse models for AML will be used to support the different theories regarding the leukemogenesis of AML. Finally, this review wants to highlight the implication of these findings for the therapy of AML.

Animals↗
PubMed2006

Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria.

A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals.

Adenine Nucleotides↗
PubMed2001

Systematic reviews: gatekeepers of nursing knowledge.

The past few decades have seen a considerable increase in the number of available health care products and interventions. This growth has been matched by a similar expansion in the health care literature. As a result of these factors, the demand for evidence to support practice is growing, but finding the best evidence is becoming increasingly difficult. In response, the use of systematic reviews is increasing and they are starting to replace the primary research as the basis for health care decisions. To date, these reviews have focused predominantly on effectiveness and so have been limited to randomized controlled trials. As a result of this, the interpretive, observational and descriptive research methods that are utilized by nursing have commonly been either excluded from the review or are classified as 'low level' evidence. To address this, nursing must participate in the development of systematic review methods that better answer the questions posed by the profession.

Attitude of Health Personnel↗
PubMed1999

The influence of gatekeeping and utilization review on patient satisfaction.

OBJECTIVE: To examine the influence of utilization review and denial of specialty referrals on patient satisfaction with overall medical care, willingness to recommend one's physician group to a friend, and desire to disenroll from the health plan. DESIGN: Two cross-sectional questionnaires: one of physician groups and one of patient satisfaction. SETTING: Eighty-eight capitated physician groups in California. PARTICIPANTS: Participants were 11,710 patients enrolled in a large California network-model HMO in 1993 who received care in one of the 88 physician groups. MEASUREMENTS AND MAIN RESULTS: Our main measures were how groups conducted utilization review for specialty referrals and tests, patient-reported denial of specialty referrals, and patient satisfaction with overall medical care. Patients in groups that required preauthorization for access to many types of specialists were significantly (p </=.001) less satisfied than patients in groups that had few preauthorization requirements, even after adjusting for patient and other group characteristics. Patients who had wanted to see a specialist in the previous year but did not see one were significantly less satisfied than those who had wanted to see a specialist and actually saw one (p <.001). In addition, patients who did not see a specialist when desired were more likely to want to disenroll from the health plan than patients who saw the specialist (40% vs 18%, p </=.001) and more likely not to recommend their group to a friend (38% vs 13%, p </=.001). CONCLUSIONS: Policies that limited direct access to specialists, and especially denial of patient-desired referrals, were associated with significantly lower patient satisfaction, increased desire to disenroll, and lower likelihood of recommending the group to a friend. Health plans and physician groups need to take these factors into account when designing strategies to reduce specialty care use.

Adolescent↗
PubMed1998

The src homology 2-containing inositol phosphatase (SHIP) is the gatekeeper of mast cell degranulation.

To clarify the role that the src homology 2-containing inositol phosphatase (SHIP) plays in mast cell degranulation, the gene for SHIP was disrupted by homologous recombination in embryonic stem cells. Bone-marrow-derived mast cells from SHIP+/+, +/-, and -/- F2 littermates were compared. SHIP-/- mast cells were found to be far more prone to degranulation, after the crosslinking of IgE preloaded cells, than SHIP+/- or +/+ cells. Intriguingly, IgE alone also stimulated massive degranulation in SHIP-/- but not in +/+ mast cells. This degranulation with IgE alone, which may be due to low levels of IgE aggregates, correlated with a higher and more sustained intracellular calcium level than that observed with SHIP+/+ cells and was dependent upon the entry of extracellular calcium. Immunoprecipitation studies revealed that the addition of IgE alone to normal mast cells stimulates multiple cascades, which are prevented from progressing to degranulation by SHIP. PI 3-kinase inhibitor studies suggested that IgE-induced activation of PI 3-kinase is upstream of the entry of extracellular calcium and that SHIP restricts this entry by hydrolyzing phosphatidylinositol 3,4, 5-trisphosphate. These results show the critical role that SHIP plays in setting the threshold for degranulation and that SHIP directly modulates a "positive-acting" receptor.

Androstadienes↗