375 research outputs found
Calcified Plaques in Patients With Acute Coronary Syndromes
OBJECTIVES: This study conducted detailed analysis of calcified culprit plaques in patients with acute coronary syndromes (ACS). BACKGROUND: Calcified plaques as an underlying pathology in patients with ACS have not been systematically studied. METHODS: From 1,241 patients presenting with ACS who had undergone pre-intervention optical coherence tomography imaging, 157 (12.7%) patients were found to have a calcified plaque at the culprit lesion. Calcified plaque was defined as a plaque with superficial calcification at the culprit site without evidence of ruptured lipid plaque. RESULTS: Three distinct types were identified: eruptive calcified nodules, superficial calcific sheet, and calcified protrusion (prevalence of 25.5%, 67.4%, and 7.1%, respectively). Eruptive calcified nodules were frequently located in the right coronary arteries (44.4%), whereas superficial calcific sheet was most frequently found in the left anterior descending coronary arteries (68.4%) (p = 0.012). Calcification index (mean calcification arc × calcification length) was greatest in eruptive calcified nodules, followed by superficial calcific sheet, and smallest in calcified protrusion (median 3,284.9 [interquartile range (IQR): 2,113.3 to 5,385.3] vs. 1,644.3 [IQR: 1,012.4 to 3,058.7] vs. 472.5 [IQR: 176.7 to 865.2]; p < 0.001). The superficial calcific sheet group had the highest peak post-intervention creatine kinase values among the groups (eruptive calcified nodules vs. superficial calcific sheet vs. calcified protrusion: 241 [IQR: 116 to 612] IU/l vs. 834 [IQR: 141 to 3,394] IU/l vs. 745 [IQR: 69 to 1,984] IU/l; p = 0.032). CONCLUSIONS: Three distinct types of calcified culprit plaques are identified in patients with ACS. Superficial calcific sheet, which is frequently located in the left anterior descending coronary artery, is the most prevalent type and is also associated with greatest post-intervention myocardial damage. (Identification of Predictors for Coronary Plaque Erosion in Patients With Acute Coronary Syndrome; NCT03479723).status: publishe
Clinical and laboratory predictors for plaque erosion in patients with acute coronary syndromes
Background-—Plaque erosion is responsible for 25% to 40% of patients with acute coronary syndromes (ACS). Recent studies
suggest that anti-thrombotic therapy without stenting may be an option for this subset of patients. Currently, however, an invasive
procedure is required to make a diagnosis of plaque erosion. The aim of this study was to identify clinical or laboratory predictors
of plaque erosion in patients with ACS to enable a diagnosis of erosion without additional invasive procedures.
Methods and Results-—Patients with ACS who underwent optical coherence tomography imaging were selected from 11
institutions in 6 countries. The patients were classified into plaque rupture, plaque erosion, or calcified plaque, and predictors were
identified using multivariable logistic modeling. Among 1241 patients with ACS, 477 (38.4%) patients were found to have plaque
erosion. Plaque erosion was more frequent in non–ST-segment elevation-ACS than in ST-segment–elevation myocardial infarction
(47.9% versus 29.8%, P=0.0002). Multivariable logistic regression models showed 5 independent parameters associated with
plaque erosion: age 15.0 g/dL, and normal renal function. When
all 5 parameters are present in a patient with non–ST-segment elevation-ACS, the probability of plaque erosion increased to 73.1%.
Conclusions-—Clinical and laboratory parameters associatedwith plaque erosion are explored in this retrospective registry study. These
parametersmay be useful to identify the subset ofACS patients with plaque erosion and guide themto conservativemanagement without
invasive procedures. The results of this exploratory analysis need to be confirmed in large scale prospective clinical studiesDr. Jang has received an educational grant from Abbott
Vascular and Medicure. Dr. Adriaenssens has received grants
and consulting fees from Abbott Vascula
Recasting the cancer stem cell hypothesis: Unification using a continuum model of microenvironmental forces
Purpose of review
Here, we identify shortcomings of standard compartment-based mathematical models of cancer stem-cells, and propose a continuous formalism which includes the tumor microenvironment.
Recent findings
Stem-cell models of tumor growth have provided explanations for various phenomena in oncology including, metastasis, drug- and radio-resistance, and functional heterogeneity in the face of genetic homogeneity. While some of the newer models allow for plasticity, or de-differentiation, there is no consensus on the mechanisms driving this. Recent experimental evidence suggests that tumor microenvironment factors like hypoxia, acidosis, and nutrient deprivation have causative roles.
Summary
To settle the dissonance between the mounting experimental evidence surrounding the effects of the microenvironment on tumor stemness, we propose a continuous mathematical model where we model microenvironmental perturbations like forces, which then shape the distribution of stemness within the tumor. We propose methods by which to systematically measure and characterize these forces, and show results of a simple experiment which support our claims
A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells
Purpose
Glioblastoma Multiforme (GBM) is the commonest brain tumour in adults. A population of cells, known as cancer stem cells (CSCs), is thought to mediate chemo/radiotherapy resistance. CD133 is a cell surface marker to identify and isolate CSCs. However, its functional significance and the relevant microenvironment in which to study CD133 remain unknown. We examined the influence of hypoxia on CD133 expression and the potential functional significance of CD133 in glioblastoma chemoresistance.
Methods
Gene expression was analysed by qRT-PCR. siRNA technique was used to downregulate genes and confirmed by flow cytometry. IC50 values was evaluated with the Alamar blue assay.
Results
CD133 expression was upregulated in hypoxia in 2D and 3D models. There was increased resistance to chemotherapeutics, cisplatin, temozolomide and etoposide, in cells cultured in hypoxia compared to normoxia. siRNA knockdown of either HIF1a or HIF2a resulted in reduced CD133 mRNA expression with HIF2a having a more prolonged effect on CD133 expression. HIF2a downregulation sensitized GBM cells to cisplatin to a greater extent than HIF1a but CD133 knockdown had a much more marked effect on cisplatin sensitisation than knockdown of either of the HIFs suggesting a HIF-independent mechanism of cisplatin resistance mediated via CD133. The same mechanism was not involved in temozolomide resistance since downregulation of HIF1a but not HIF2a or CD133 sensitized GBM cells to temozolomide.
Conclusion
Knowledge of the mechanisms involved in the novel hypoxia-induced CD133-mediated resistance to cisplatin observed might lead to identification of new strategies that enable more effective use of current therapeutic agents
Sulforaphane restores cellular glutathione levels and reduces chronic periodontitis neutrophil hyperactivity in vitro
The production of high levels of reactive oxygen species by neutrophils is associated with the local and systemic destructive phenotype found in the chronic inflammatory disease periodontitis. In the present study, we investigated the ability of sulforaphane (SFN) to restore cellular glutathione levels and reduce the hyperactivity of circulating neutrophils associated with chronic periodontitis. Using differentiated HL60 cells as a neutrophil model, here we show that generation of extracellular O2 . - by the nicotinamide adenine dinucleotide (NADPH) oxidase complex is increased by intracellular glutathione depletion. This may be attributed to the upregulation of thiol regulated acid sphingomyelinase driven lipid raft formation. Intracellular glutathione was also lower in primary neutrophils from periodontitis patients and, consistent with our previous findings, patients neutrophils were hyper-reactive to stimuli. The activity of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of the antioxidant response, is impaired in circulating neutrophils from chronic periodontitis patients. Although patients' neutrophils exhibit a low reduced glutathione (GSH)/oxidised glutathione (GSSG) ratio and a higher total Nrf2 level, the DNA-binding activity of nuclear Nrf2 remained unchanged relative to healthy controls and had reduced expression of glutamate cysteine ligase catalytic (GCLC), and modifier (GCLM) subunit mRNAs, compared to periodontally healthy subjects neutrophils. Pre-treatment with SFN increased expression of GCLC and GCM, improved intracellular GSH/GSSG ratios and reduced agonist-activated extracellular O2 . - production in both dHL60 and primary neutrophils from patients with periodontitis and controls. These findings suggest that a deficiency in Nrf2-dependent pathways may underpin susceptibility to hyper-reactivity in circulating primary neutrophils during chronic periodontitis. © 2013 Dias et al
A genetic locus and gene expression patterns associated with the priming effect on lettuce seed germination at elevated temperatures
Seeds of most cultivated varieties of lettuce (Lactuca sativa L.) fail to germinate at warm temperatures (i.e., above 25–30°C). Seed priming (controlled hydration followed by drying) alleviates this thermoinhibition by increasing the maximum germination temperature. We conducted a quantitative trait locus (QTL) analysis of seed germination responses to priming using a recombinant inbred line (RIL) population derived from a cross between L. sativa cv. Salinas and L. serriola accession UC96US23. Priming significantly increased the maximum germination temperature of the RIL population, and a single major QTL was responsible for 47% of the phenotypic variation due to priming. This QTL collocated with Htg6.1, a major QTL from UC96US23 associated with high temperature germination capacity. Seeds of three near-isogenic lines (NILs) carrying an Htg6.1 introgression from UC96US23 in a Salinas genetic background exhibited synergistic increases in maximum germination temperature in response to priming. LsNCED4, a gene encoding a key enzyme (9-cis-epoxycarotinoid dioxygenase) in the abscisic acid biosynthetic pathway, maps precisely with Htg6.1. Expression of LsNCED4 after imbibition for 24 h at high temperature was greater in non-primed seeds of Salinas, of a second cultivar (Titan) and of NILs containing Htg6.1 compared to primed seeds of the same genotypes. In contrast, expression of genes encoding regulated enzymes in the gibberellin and ethylene biosynthetic pathways (LsGA3ox1 and LsACS1, respectively) was enhanced by priming and suppressed by imbibition at elevated temperatures. Developmental and temperature regulation of hormonal biosynthetic pathways is associated with seed priming effects on germination temperature sensitivity
Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma
Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology
Imbalance of neuronal proteostasis associated with misfolding and aggregation of Tau protein is a common neurodegenerative feature in Alzheimer's disease (AD) and other Tauopathies. Consistent with suggestions that lifetime stress may be an important AD precipitating factor, we previously reported that environmental stress and high glucocorticoid (GC) levels induce accumulation of aggregated Tau; however, the molecular mechanisms for such process remain unclear. Herein, we monitor a novel interplay between RNA-binding proteins (RBPs) and autophagic machinery in the underlying mechanisms through which chronic stress and high GC levels impact on Tau proteostasis precipitating Tau aggregation. Using molecular, pharmacological and behavioral analysis, we demonstrate that chronic stress and high GC trigger mTOR-dependent inhibition of autophagy, leading to accumulation of Tau aggregates and cell death in P301L-Tau expressing mice and cells. In parallel, we found that environmental stress and GC disturb cellular homeostasis and trigger the insoluble accumulation of different RBPs, such as PABP, G3BP1, TIA-1, and FUS, shown to form stress granules (SGs) and Tau aggregation. Interestingly, an mTOR-driven pharmacological stimulation of autophagy attenuates the GC-driven accumulation of Tau and SG-related proteins as well as the related cell death, suggesting a critical interface between autophagy and the response of the SG-related protein in the neurodegenerative potential of chronic stress and GC. These studies provide novel insights into the RNA-protein intracellular signaling regulating the precipitating role of environmental stress and GC on Tau-driven brain pathology.We would like to thank Professor Juergen Gotz, (University of Queensland, Australia) for the kind offer of eGFP-P301LTau SH-SY5Y cells and Dr. Bruno Almeida for his technical assistance. J.M.S. was granted with a PhD fellowship (SRFH/BD/88932/2012) by Portuguese Foundation for Science & Technology (FCT); I.S. is holder of FCT Investigator grants (IF/01799/2013), C.D. is a recipient of PhD fellowship of PHDoc program and co-tutelle PhD student of UMinho-UPMC universities. This work was funded by FCT research grants "PTDC/SAU-NMC/113934/2009" (I.S.), the Portuguese North Regional Operational Program (ON. 2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER) as well as the Project Estrategico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298) as well as the project NORTE-01-0145-FEDER000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). In addition, this work was partly funded by Canon Foundation in Europe. This work has been also funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145FEDER-007038. This study was also supported to BW by grants from NIH (AG050471, NS089544, and ES020395), the BrightFocus Foundation, the Alzheimer Association and the Cure Alzeimer Foundation. Human brain tissue was generously provided by the National Institute of Aging Boston University AD Center (P30AG13846).info:eu-repo/semantics/publishedVersio
Seed priming and sulfur effects on soybean cell membrane stability and yield in saline soil
- …