587 research outputs found
Biomarkers in acute coronary syndromes and their role in diabetic patients
Diabetic patients with acute coronary syndromes
are at high risk for cardiovascular complications
but risk stratification in these patients remains
challenging. Regularly, diabetic patients have a less typical
clinical presentation, which could lead to delayed
diagnosis and subsequent delayed initiation of treatment.
Since diabetic patients derive particular benefit
from aggressive anti-platelet therapy, early diagnostic
and therapeutic risk stratification of these patients is of
critical importance to improve their adverse outcome.
Although the electrocardiogram remains a pivotal
diagnostic tool in the evaluation of patients suspected of
having an acute coronary syndrome, only significant STsegment
changes provide reasonable prognostic information.
Therefore, repeated assessment of circulating
protein biomarkers represents a valuable diagnostic tool
for improving efficacy and safety of decision-making in
these patients. The combined use of biomarkers reflecting
distinct pathophysiological aspects, such as myocardial
necrosis, vascular inflammation, oxidative stress
and neurohumoral activation, may significantly improve
triage of patients with chest pain. These tools may identify
those patients that are at particularly high risk for
short-term and/or long-term cardiovascular events.
Eventually, tailored medical and interventional treatment
of diabetic patients should help to prevent these cardiac
events in a cost-effective manner
Recommended from our members
Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells
Background— Transplantation of ex vivo expanded circulating endothelial progenitor cells (EPCs) from peripheral blood mononuclear cells improves the neovascularization after critical ischemia. However, the origin of the endothelial progenitor lineage and its characteristics have not yet been clearly defined. Therefore, we investigated whether the phenotype and functional capacity of EPCs to improve neovascularization depend on their monocytic origin
Recommended from our members
Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia
Background— Stem and progenitor cell therapy is a novel approach to improve neovascularization and function of ischemic tissue. Enhanced tissue expression of chemoattractant factors such as stromal cell–derived factor 1 and vascular endothelial growth factor is crucial for the recruitment of circulating endothelial progenitor cells (EPCs) during acute ischemia. In chronic ischemia, however, expression of these chemoattractants is less pronounced, which results in insufficient EPC recruitment into the target tissue. Therefore, we investigated the effect of targeted extracorporeal shock wave (SW) application in order to facilitate EPC recruitment into nonischemic and chronic ischemic tissue
Nicotine strongly activates dendritic cell-mediated adaptive immunity - potential role for progression of atherosclerotic lesions
Background - Antigen-presenting cells (APCs) such as monocytes and dendritic cells (DCs) stimulate T-cell proliferation and activation in the course of adaptive immunity. This cellular interaction plays a role in the growth of atherosclerotic plaques. Nicotine has been shown to increase the growth of atherosclerotic lesions. Therefore, we investigated whether nicotine can stimulate APCs and their T cell–stimulatory capacity using human monocyte–derived DCs and murine bone marrow–derived DCs as APCs. Methods and Results - Nicotine dose-dependently (10-8 to 10-4 mol/L) induced DC expression of costimulatory molecules (ie, CD86, CD40), MHC class II, and adhesion molecules (ie, LFA-1, CD54). Moreover, nicotine induced a 7.0-fold increase in secretion of the proinflammatory TH1 cytokine interleukin-12 by human DCs. These effects were abrogated by the nicotinic receptor antagonist -bungarotoxin and mecamylamine, respectively. The effects of nicotine were mediated in part by the phosphorylation of the PI3 kinase downstream target Akt and the mitogen-activated kinases ERK and p38 MAPK. Nicotine-stimulated APCs had a greater capacity to stimulate T-cell proliferation and cytokine secretion, as documented by mixed lymphocyte reactions and ovalbumin-specific assays with ovalbumin-transgenic DO10.11 mice. In a murine model of atherosclerosis, nicotine significantly enhanced the recruitment of DCs to atherosclerotic lesions in vivo. Conclusions - Nicotine activates DCs and augments their capacity to stimulate T-cell proliferation and cytokine secretion. These effects of nicotine may contribute to its influence on the progression of atherosclerotic lesions
Prostaglandin E Positively Modulates Endothelial Progenitor Cell Homeostasis: An Advanced Treatment Modality for Autologous Cell Therapy
Aims: The mobilization of endothelial progenitor cells (EPC) and their functioning in postnatal neovascularization are tightly regulated. To identify new modulators of EPC homeostasis, we screened biologically active prostaglandin E compounds for their effects on EPC production, trafficking and function. Methods and Results: We found that EPC are a rich source for prostaglandin E 2 (PGE 2), stimulating their number and function in an auto- and paracrine manner. In vivo blockade of PGE 2 production by selective cyclooxygenase-2 inhibition virtually abrogated ischemia-induced EPC mobilization demonstrating its crucial role in EPC homeostasis following tissue ischemia. Conversely, ex vivo treatment of isolated EPC with the clinically approved PGE 1 analogue alprostadil enhanced EPC number and function. These effects were mediated by increased expression of the chemokine receptor CXCR4 and were dependent on nitric oxide synthase activity. Most importantly, ex vivo PGE 1 pretreatment of isolated EPC significantly enhanced their neovascularization capacity in a murine model of hind limb ischemia as assessed by laser Doppler analysis, exercise stress test and immunohistochemistry. Conclusions: The conserved role for PGE in the regulation of EPC homeostasis suggests that ex vivo modulation of the prostaglandin pathway in isolated progenitor cells may represent a novel and safe strategy to facilitate cell-based therapies. Copyright (C) 2009 S. Karger AG, Base
Recommended from our members
Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease
Background— Cell therapy with bone marrow–derived stem/progenitor cells is a novel option for improving neovascularization and cardiac function in ischemic heart disease. Circulating endothelial progenitor cells in patients with coronary heart disease are impaired with respect to number and functional activity. However, whether this impairment also extends to bone marrow–derived mononuclear cells (BM-MNCs) in patients with chronic ischemic cardiomyopathy (ICMP) is unclea
The Shroud Around the Twin Radio Jets in NGC 1052
(Abridged) We discuss multiple VLBI continuum and spectral line observations
and WSRT spectroscopy of NGC 1052. Sub-parsec scale features move outward at
approximately 0.26c in bi-symmetric jets, most likely oriented near the plane
of the sky. Absorption and emission signatures reveal ionised, atomic, and
molecular components of the surrounding medium.
Seven-frequency (1.4 to 43 GHz) VLBA observations show free-free absorption
in the inner parsec, probably together with synchrotron self-absorption. There
is apparently a geometrically thick but patchy structure oriented roughly
orthogonal to the jets. The western jet is receding: it is covered more deeply
and extensively. HI spectral line VLBI reveals atomic gas in front of both
jets. There appear to be three velocity systems. The deepest, at "high
velocities" (receding by 125 to 200 km/s), seems restricted to a shell 1 to 2
pc away from the core, within which this gas might be largely ionised. WSRT
spectroscopy has revealed 1667 and 1665 MHz OH absorption with their line ratio
varying roughly from 1:1 to 2:1 between -35 and 200 km/s. In the high velocity
system the OH profiles are similar to HI, suggesting co-location of that atomic
and molecular gas, and leaving unclear the connection to the H2O masing gas
seen elsewhere. We have also detected both 18cm OH satellite lines in the high
velocity system. They have conjugate profiles: 1612 MHz is in absorption, and
1720 MHz in emission.Comment: 16 pages, 14 figures, LaTeX, includes aa.cls, accepted for
publication in Astronomy and Astrophysic
Glutathione metabolism is essential for self-renewal and chemoresistance of pancreatic cancer stem cells
BACKGROUND
Cellular metabolism regulates stemness in health and disease. A reduced redox state is essential for self-renewal of normal and cancer stem cells (CSCs). However, while stem cells rely on glycolysis, different CSCs, including pancreatic CSCs, favor mitochondrial metabolism as their dominant energy-producing pathway. This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species (ROS) and maintain stemness in oxidative CSCs. Since glutathione metabolism is critical for normal stem cell function and CSCs from breast, liver and gastric cancer show increased glutathione content, we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification. AIM To investigate the role of glutathione metabolism in pancreatic CSCs.
METHODS
Primary pancreatic cancer cells of patient-derived xenografts (PDXs) were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness. Real-time polymerase chain reaction (PCR) was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres, as well as the expression of pluripotency-related genes following treatment. Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2. The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry. Pharmacological inhibitors of glutathione synthesis and recycling [buthionine-sulfoximine (BSO) and 6-Aminonicotinamide (6-AN), respectively] were used to investigate the impact of glutathione depletion on CSC-enriched cultures. Staining with propidium iodide (cell cycle), Annexin-V (apoptosis) and CD133 (CSC content) were determined by flow cytometry. Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.
RESULTS
Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed up-regulation of genes involved in the KEGG (Kyoto Encyclopedia of Genes and Genomes) Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts. Consistently, in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG, KLF4, SOX2 and OCT4 expression (P < 10-5). Moreover, 3 of the upregulated genes (MGST1, GPX8, GCCT) were associated with reduced disease-free survival in patients [Hazard ratio (HR) 2.2-2.5; P = 0.03-0.0054], suggesting a critical role for this pathway in pancreatic cancer progression. CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes, as well as enhanced glutathione content in its reduced form (GSH). Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres, and diminished the expression of stemness genes. Moreover, treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133. GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r = 0.96, P = 5.8 Ă— 1011). Additionally, CD133+ cells accumulated GSH in response to gemcitabine, which was abrogated by BSO treatment (P < 0.05). Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+ cells to levels comparable to CD133- cells and significantly diminished self-renewal (P < 0.05), suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.
CONCLUSION
Our data suggest that pancreatic CSCs depend on glutathione metabolism. Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance
Linguistics
Contains reports on four research projects.U. S. Air Force (Electronics Systems Division) under Contract AF 19(628)-2487Joint Services Electronics Programs (U.S. Army, U.S. Navy, and U.S. Air Force) under Contract DA 28-043-AMC-02536(E)National Science Foundation (Grant GK-835)National Institutes of Health (Grant 2 PO1 MH-04737-06)National Aeronautics and Space Administration (Grant NsG-496
Angiographic findings in patients with refractory unstable angina according to troponin T status
BACKGROUND: The CAPTURE (C7E3 fab AntiPlatelet Therapy in Unstable
REfactory angina) trial enrolled patients with refractory unstable angina
and documented a therapeutic benefit for abciximab, a platelet
glycoprotein IIb/IIIa receptor antagonist, that was particularly evident
in patients with elevated troponin T (TnT) levels. In the current study,
we related the angiographic data to the TnT status of the CAPTURE
patients. METHODS AND RESULTS: In 853 patients, angiographic data at
baseline and 18 to 24 hours after treatment were available and assessed by
an Angiographic Committee with respect to TIMI flow, lesion severity, and
visibility of thrombus. TnT levels >0.1 microg/L were found in 30.9% of
the patients. Before randomization, thrombus was visible in 14.6% of
TnT-positive patients (TnT levels >0.1 microg/L) and 4.2% of TnT-negative
patients (P=0.004). Complex lesion characteristics B2+/C (72.0% versus
53.9%; P<0.001) and TIMI flow <2 (15.6% versus 5. 1%; P<0.001) were more
frequent in TnT-positive patients. Abciximab was effective with respect to
reduction of visible thrombus, increase of TIMI flow, and reduction of
cardiac events in TnT-positive patients only. Multivariate analysis
identified TnT status, but not angiographic findings, as an independent
predictor for both outcome and efficacy of treatment with abciximab.
CONCLUSIONS: Complex lesion characteristics and visible thrombus formation
at baseline were significantly linked to TnT elevation. However, TnT
st
- …