Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelets play an important role in the pathophysiology of acute myocardial infarction, unstable angina, and ischemic stroke. The expression of the glycoprotein IIb/IIIa (alphaIIb/beta3 integrin) receptor on the surface of activated platelets constitutes the common pathway for platelet aggregation. Glycoprotein IIb/IIIa has low affinity for its soluble ligands (fibrinogen and von Willebrand factor) in resting platelets. In the setting of vascular injury, platelet activation occurs after binding of the glycoprotein Ib-IX-V receptor to von Willebrand factor in the extracellular matrix (at high shear rate) and binding of soluble agonists to specific platelet membrane receptors. The ensuing inside-out signaling increases several-fold the affinity and avidity of alphaIIb/beta3 for its ligands. High affinity ligand binding to alphaIIb/beta3 triggers outside-in signaling, causing microskeletal contraction and platelet retraction. The signaling pathways for inside-out and outside-in signaling are incompletely understood. Glycoprotein IIb/IIIa antagonists were developed under the premise that these agents would abrogate platelet aggregation while preserving platelet monolayer deposition at sites of injury. A number of parenteral and oral agents have been developed and evaluated in clinical trials. Three of them are approved in the United States and other countries: abciximab (ReoPro; the Fab fragment of a chimeric human-mouse antibody), eptifibatide (Integrelin; a cyclic heptapeptide), and tirofiban (Aggrastat; a tyrosine-derived nonpeptide molecule). The greatest clinical impact of these parenteral agents (used in conjunction with aspirin and heparin) has been in the prevention of ischemic complications after percutaneous coronary intervention. In contrast, oral agents have yielded disappointing results in the secondary prevention of acute coronary syndromes, and none of them are approved at present. Eptifibatide and tirofiban are specific for alphaIIb/beta3, whereas abciximab also exhibits cross-reactivity with the alphavbeta3 and alphaMbeta2 integrins. Although alphaIIb/beta3 is unique to platelets and megakaryocytes, alphavbeta3 is more widely distributed and mediates several functions, including endothelial cell migration, monocyte adhesion, angiogenesis, and inhibition of apoptosis. alphaMbeta2 mediates leukocyte-platelet interactions. In the percutaneous coronary intervention trials, abciximab has been more efficacious than the other parenteral agents, perhaps because of cross-reactivity with these other integrins, the pharmacodynamic profile of abciximab, or other effects. Other documented effects of abciximab include acute dethrombosis, reduction of thrombin generation, and improved flow in the coronary microcirculation after percutaneous coronary intervention. Abciximab is presently under evaluation in the treatment of acute ischemic stroke. Promising data have been obtained in experimental models of tumor angiogenesis and sickle cell anemia.
 ...
PMID:Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions. 1200 56

Conventional stroke risks are thought responsible for most cerebral ischemic events (CIE) in adult cancer patients. Also suspected as a risk is cisplatin chemotherapy, alone or in combination with tumor angiogenesis inhibitor. We investigated whether treatment or tumor characteristics, independently of conventional stroke risks, are associated with CIE in a retrospective cohort study of 1,559 patients with advanced non-small cell lung cancer or hormone-refractory prostate cancer followed during 3 clinical trials of matrix metalloprotease inhibitor (prinomastat) versus placebo, with chemotherapy (gemcitabine/cisplatin, paclitaxel/carboplatin or mitoxantrone/prednisone). During 11,907 patient-months, 28 CIE (17 cerebral infarction, 11 transient ischemic attack) were diagnosed in 24 patients, all but 1 over 55 years. Neither prinomastat, platinum-based chemotherapy nor their combination was associated with CIE after age 55. However, such events were predicted by the presence of distant metastases in the liver or lungs and not in distant lymph nodes (hazard estimate 4.6, 95% CI 2.0-10.5, adjusted for conventional stroke risks). Further studies are needed to verify this preliminary finding and determine its generalizability to advanced tumors other than lung or prostate cancer.
 ...
PMID:Cerebral ischemic events in patients with advanced lung or prostate cancer. 1583 61

Aquaporins (AQPs) are membrane proteins that transport water and, in some cases, also small solutes such as glycerol. AQPs are expressed in many fluid-transporting tissues, such as kidney tubules and glandular epithelia, as well as in non-fluid-transporting tissues, such as epidermis, adipose tissue and astroglia. Their classical role in facilitating trans-epithelial fluid transport is well understood, as in the urinary concentrating mechanism and gland fluid secretion. AQPs are also involved in swelling of tissues under stress, as in the injured cornea and the brain in stroke, tumor and infection. Recent analysis of AQP-knockout mice has revealed unexpected cellular roles of AQPs. AQPs facilitate cell migration, as manifested by reduced tumor angiogenesis in AQP1-knockout mice, by a mechanism that might involve facilitated water transport in lamellipodia of migrating cells. AQPs that transport both glycerol and water regulate glycerol content in epidermis and fat, and consequently skin hydration/biosynthesis and fat metabolism. AQPs might also be involved in neural signal transduction, cell volume regulation and organellar physiology. The many roles of AQPs could be exploited for clinical benefit; for example, treatments that modulate AQP expression/function could be used as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer.
 ...
PMID:More than just water channels: unexpected cellular roles of aquaporins. 1607 75

Interactions between endothelial cells and mural cells (pericytes and vascular smooth muscle cells) in the blood vessel wall have recently come into focus as central processes in the regulation of vascular formation, stabilization, remodeling, and function. Failure of the interactions between the 2 cell types, as seen in numerous genetic mouse models, results in severe and often lethal cardiovascular defects. Abnormal interactions between the 2 cell types are also implicated in a number of human pathological conditions, including tumor angiogenesis, diabetic microangiopathy, ectopic tissue calcification, and stroke and dementia syndrome CADASIL. In the present review, we summarize current knowledge concerning the identity, characteristics, diversity, ontogeny, and plasticity of pericytes. We focus on the advancement in recent years of the understanding of intercellular communication between endothelial and mural cells with a focus on transforming growth factor beta, angiopoietins, platelet-derived growth factor, spingosine-1-phosphate, and Notch ligands and their respective receptors. We finally highlight recent important data contributing to the understanding of the role of pericytes in tumor angiogenesis, diabetic retinopathy, and hereditary lymphedema.
 ...
PMID:Endothelial/pericyte interactions. 1616 62

Vascular endothelial growth factor (VEGF) signaling is critical for both normal and disease-associated vascular development. Dysregulated VEGF signaling has been implicated in ischemic stroke, tumor angiogenesis, and many other vascular diseases. VEGF signals through several effectors, including the Rho family of small GTPases. As a member of this family, Rac1 promotes VEGF-induced endothelial cell migration by stimulating the formation of lamellipodia and membrane ruffles. To form these membrane protrusions, Rac1 is activated by guanine nucleotide exchange factors (GEFs) that catalyze the exchange of GDP for GTP. The goal of this study was to identify the GEF responsible for activating Rac1 in response to VEGF stimulation. We have found that VEGF stimulates biphasic activation of Rac1 and for these studies we focused on the peak of activation that occurs at 30 min. Inhibition of VEGFR-2 signaling blocks VEGF-induced Rac1 activation. Using a Rac1 nucleotide-free mutant (G15ARac1), which has a high affinity for binding activated GEFs, we show that the Rac GEF Vav2 associates with G15ARac1 after VEGF stimulation. Additionally, we show that depleting endothelial cells of endogenous Vav2 with siRNA prevents VEGF-induced Rac1 activation. Moreover, Vav2 is tyrosine phosphorylated upon VEGF treatment, which temporally correlates with Rac1 activation and requires VEGFR-2 signaling and Src kinase activity. Finally, we show that depressing Vav2 expression by siRNA impairs VEGF-induced endothelial cell migration. Taken together, our results provide evidence that Vav2 acts downstream of VEGF to activate Rac1.
 ...
PMID:VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2. 1768 71

Vascular assembly, patterning, and maintenance is a complex and highly regulated process that begins with the formation of a primary capillary plexus by means of angiogenesis or vasculogenesis and ends when the primitive vessels have been remodeled into quiescent, differentiated vessels. Differentiated or "mature" microvessels are characterized in large part by their association with pericytes, and failure of these interactions results in severe, and often lethal, defects that have been implicated in a number of human pathologic conditions, including tumor angiogenesis, diabetic microangiopathy, ectopic tissue calcification, stroke, and dementia. This chapter describes methods that can be used to isolate and culture primary pericytes, as well as to study pericyte-endothelial cell interactions with in vitro cell culture systems.
 ...
PMID:Pericyte isolation and use in endothelial/pericyte coculture models. 1877 23

Knockout mice have been informative in the discovery of unexpected biological functions of aquaporins. Knockout mice have confirmed the predicted roles of aquaporins in transepithelial fluid transport, as in the urinary concentrating mechanism and glandular fluid secretion. A less obvious, though predictable role of aquaporins is in tissue swelling under stress, as in the brain in stroke, tumor and infection. Phenotype analysis of aquaporin knockout mice has revealed several unexpected cellular roles of aquaporins whose mechanisms are being elucidated. Aquaporins facilitate cell migration, as seen in aquaporin-dependent tumor angiogenesis and tumor metastasis, by a mechanism that may involve facilitated water transport in lamellipodia of migrating cells. The ' aquaglyceroporins', aquaporins that transport both glycerol and water, regulate glycerol content in epidermis, fat and other tissues, and lead to a multiplicity of interesting consequences of gene disruption including dry skin, resistance to skin carcinogenesis, impaired cell proliferation and altered fat metabolism. An even more surprising role of a mammalian aquaporin is in neural signal transduction in the central nervous system. The many roles of aquaporins might be exploited for clinical benefit by modulation of aquaporin expression/function - as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer.
 ...
PMID:Knock-out models reveal new aquaporin functions. 1909 87

Measuring the morphology of the cerebral microvasculature by vessel-size imaging (VSI) is a promising approach for clinical applications, such as the characterization of tumor angiogenesis and stroke. Despite the great potential of VSI, this method has not yet found widespread use in practice due to the lack of experience in testing it on healthy humans. Since this limitation derives mainly from the need for an invasive injection of a contrast agent, this work explores the possibility to employ instead the easily accessible blood oxygenation level dependent (BOLD) effect for VSI of the venous microstructure. It is demonstrated that BOLD-VSI in humans can be realized by a hypercapnic challenge using a fast gradient-echo (GE) and spin-echo (SE) sequence at 7T. Reproducible maps of the mean venous vessel radius, based on the BOLD-induced changes in GE and SE relaxation rates, could be obtained within a scan time of 10min. Moreover, the method yields maps of venous blood volume and vessel density. Owing to its non-invasive character, BOLD-VSI provides a low-risk method to analyze the venous microstructure, which will not only be useful in clinical applications, but also provide a better understanding of BOLD effect.
 ...
PMID:Whole-brain mapping of venous vessel size in humans using the hypercapnia-induced BOLD effect. 2018 89

Dr. Feng Chen is a chief medical doctor and the vice chairman of the Department of Radiology in Zhong Da Hospital at Southeast University, Nanjing, China and a senior researcher in the Department of Radiology at the Catholic University of Leuven, Belgium. His main areas of interest are translational imaging research including stroke, tumor angiogenesis, assessment of therapeutic response in solid tumors, and magnetic resonance contrast media. Dr. Feng Chen has published 44 scientific papers in peer-reviewed international journals. He and his colleagues have developed an imaging platform which includes animal models, animal preparations and multiparametric magnetic resonance imaging (MRI) protocols for translational animal imaging research using clinical machines. His MRI findings on rodent stroke are considered to "serve as a model for future laboratory investigations of treatment of acute stroke and unify the approaches developed for clinical studies". He and his colleagues have introduced a novel liver tumor model in rodents, in which a series of studies concerning the antitumor activity of vascular disrupting agents have been successively conducted and assessed by in vivo MRI, especially by diffusion weighted imaging as an imaging biomarker. His goal is to provide valuable references for clinical practice and to contribute to the translation of animal imaging research into patient applications.
 ...
PMID:Feng Chen's work on translational and clinical imaging. 2153 73

The evolution in our understanding of tumor angiogenesis has been the result of pioneering imaging and computational modeling studies spanning the endothelial cell, microvasculature and tissue levels. Many of these primary data on the tumor vasculature are in the form of images from pre-clinical tumor models that provide a wealth of qualitative and quantitative information in many dimensions and across different spatial scales. However, until recently, the visualization of changes in the tumor vasculature across spatial scales remained a challenge due to a lack of techniques for integrating micro- and macroscopic imaging data. Furthermore, the paucity of three-dimensional (3-D) tumor vascular data in conjunction with the challenges in obtaining such data from patients presents a serious hurdle for the development and validation of predictive, multiscale computational models of tumor angiogenesis. In this review, we discuss the development of multiscale models of tumor angiogenesis, new imaging techniques capable of reproducing the 3-D tumor vascular architecture with high fidelity, and the emergence of "image-based models" of tumor blood flow and molecular transport. Collectively, these developments are helping us gain a fundamental understanding of the cellular and molecular regulation of tumor angiogenesis that will benefit the development of new cancer therapies. Eventually, we expect this exciting integration of multiscale imaging and mathematical modeling to have widespread application beyond the tumor vasculature to other diseases involving a pathological vasculature, such as stroke and spinal cord injury.
 ...
PMID:Multiscale imaging and computational modeling of blood flow in the tumor vasculature. 2256 17


1 2 Next >>