Evaluation of atherosclerotic lesions in cholesterol-fed mice during treatment with paclitaxel in lipid nanoparticles: a magnetic resonance imaging study.
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ABSTRACT:
SUBMITTER: D Lima A
PROVIDER: S-EPMC5445214 | biostudies-other | 2017 Jan
REPOSITORIES: biostudies-other
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Project description:Genome wide DNA methylation profiling of normal and tumour prostate samples. The Illumina Infinium MethylationEPIC Human DNA methylation oligonucleotide beads was used to obtain DNA methylation profiles across approximately 850,000 CpGs. Comparative assessment was carried out.
2018-12-01 | GSE101908 | GEO
Project description:BackgroundThe hallmark of atherosclerosis is the accumulation of plaque in vessel walls. This process is initiated when monocytic cells differentiate into macrophage foam cells under conditions with high levels of atherogenic lipoproteins. Vulnerable plaque can dislodge, enter the blood stream, and result in acute myocardial infarction and stroke. Imaging techniques such as cardiovascular magnetic resonance (CMR) provides one strategy to identify patients with plaque accumulation.MethodsWe synthesized an atherosclerotic-targeting contrast agent (ATCA) in which gadolinium (Gd)-containing endohedrals were functionalized and formulated into liposomes with CD36 ligands intercalated into the lipid bilayer. In vitro assays were used to assess the specificity of the ATCA for foam cells. The ability of ATCA to detect atherosclerotic plaque lesions in vivo was assessed using CMR.ResultsThe ATCA was able to detect scavenger receptor (CD36)-expressing foam cells in vitro and were specifically internalized via the CD36 receptor as determined by focused ion beam/scanning electron microscopy (FIB-SEM) and Western blotting analysis of CD36 receptor-specific signaling pathways. The ATCA exhibited time-dependent accumulation in atherosclerotic plaque lesions of ApoE -/- mice as determined using CMR. No ATCA accumulation was observed in vessels of wild type (C57/b6) controls. Non-targeted control compounds, without the plaque-targeting moieties, were not taken up by foam cells in vitro and did not bind plaque in vivo. Importantly, the ATCA injection was well tolerated, did not demonstrate toxicity in vitro or in vivo, and no accumulation was observed in the major organs.ConclusionsThe ATCA is specifically internalized by CD36 receptors on atherosclerotic plaque providing enhanced visualization of lesions under physiological conditions. These ATCA may provide new tools for physicians to non-invasively detect atherosclerotic disease.
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Project description:Melanoma is the most aggressive and metastasis-prone form of skin cancer. Conventional therapies include chemotherapeutic agents, either as small molecules or carried by FDA-approved nanostructures. However, systemic toxicity and side effects still remain as major drawbacks. With the advancement of nanomedicine, new delivery strategies emerge at a regular pace, aiming to overcome these challenges. Stimulus-responsive drug delivery systems might considerably reduce systemic toxicity and side-effects by limiting drug release to the affected area. Herein, we report the development of paclitaxel-loaded lipid-coated manganese ferrite magnetic nanoparticles (PTX-LMNP) as magnetosomes synthetic analogs, envisaging the combined chemo-magnetic hyperthermia treatment of melanoma. PTX-LMNP physicochemical properties were verified, including their shape, size, crystallinity, FTIR spectrum, magnetization profile, and temperature profile under magnetic hyperthermia (MHT). Their diffusion in porcine ear skin (a model for human skin) was investigated after intradermal administration via fluorescence microscopy. Cumulative PTX release kinetics under different temperatures, either preceded or not by MHT, were assessed. Intrinsic cytotoxicity against B16F10 cells was determined via neutral red uptake assay after 48 h of incubation (long-term assay), as well as B16F10 cells viability after 1 h of incubation (short-term assay), followed by MHT. PTX-LMNP-mediated MHT triggers PTX release, allowing its thermal-modulated local delivery to diseased sites, within short timeframes. Moreover, half-maximal PTX inhibitory concentration (IC50) could be significantly reduced relatively to free PTX (142,500×) and Taxol® (340×). Therefore, the dual chemo-MHT therapy mediated by intratumorally injected PTX-LMNP stands out as a promising alternative to efficiently deliver PTX to melanoma cells, consequently reducing systemic side effects commonly associated with conventional chemotherapies.
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Project description:BACKGROUND:The presence of intraplaque haemorrhage (IPH) has been related to plaque rupture, is associated with plaque progression, and predicts cerebrovascular events. However, the mechanisms leading to IPH are not fully understood. The dominant view is that IPH is caused by leakage of erythrocytes from immature microvessels. The aim of the present study was to investigate whether there is an association between atherosclerotic plaque microvasculature and presence of IPH in a relatively large prospective cohort study of patients with symptomatic carotid plaque. METHODS:One hundred and thirty-two symptomatic patients with ?2?mm carotid plaque underwent cardiovascular magnetic resonance (CMR) of the symptomatic carotid plaque for detection of IPH and dynamic contrast-enhanced (DCE)-CMR for assessment of plaque microvasculature. Ktrans, an indicator of microvascular flow, density and leakiness, was estimated using pharmacokinetic modelling in the vessel wall and adventitia. Statistical analysis was performed using an independent samples T-test and binary logistic regression, correcting for clinical risk factors. RESULTS:A decreased vessel wall Ktrans was found for IPH positive patients (0.051?±?0.011?min-?1 versus 0.058?±?0.017?min-?1, p?=?0.001). No significant difference in adventitial Ktrans was found in patients with and without IPH (0.057?±?0.012?min-?1 and 0.057?±?0.018?min-?1, respectively). Histological analysis in a subgroup of patients that underwent carotid endarterectomy demonstrated no significant difference in relative microvessel density between plaques without IPH (n?=?8) and plaques with IPH (n?=?15) (0.000333?±?0.0000707 vs. and 0.000289?±?0.0000439, p?=?0.585). CONCLUSIONS:A reduced vessel wall Ktrans is found in the presence of IPH. Thus, we did not find a positive association between plaque microvasculature and IPH several weeks after a cerebrovascular event. Not only leaky plaque microvessels, but additional factors may contribute to IPH development. TRIAL REGISTRATION:NCT01208025 . Registration date September 23, 2010. Retrospectively registered (first inclusion September 21, 2010). NCT01709045 , date of registration October 17, 2012. Retrospectively registered (first inclusion August 23, 2011).
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Project description:Oxidized phosphatidylcholines (oxPCs) enriched on the oxidized LDL (oxLDL) surface are responsible ligands for binding oxLDL to the CD36 receptor of intimal macrophages in atherosclerotic lesions. We synthesized liposome-like nanoparticles (NPs) using soy phosphatidylcholine and incorporated 1-palmitoyl-2-(4-keto-dodec-3-enedioyl) phosphatidylcholine, a type of oxPCs, on their surface to make ligand-NP (L-NPs). The objectives of this study were to measure and compare their binding affinity to and uptake by primary mouse and THP-1 derived macrophages, and to determine their target specificity to intimal macrophages in aortic lesions in LDL receptor null (LDLr-/-) mice. All in vitro data demonstrate that L-NPs had a high binding affinity to macrophage CD36 receptor. L-NPs had 1.4-fold higher accumulation in aortic lesion areas than NPs. L-NPs co-localized with intimal macrophages and CD36 receptors in the aortic lesions. This target delivery approach may portend a breakthrough in molecular imaging and targeted treatment of atherosclerosis.
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Project description:The aim of this work was to assess the effect of chronic administration of protonated nanostructured aluminosilicate (NSAS) on the plasma cholesterol levels and development of atherosclerotic lesions in Apolipoprotein (ApoE) deficient mice fed a high cholesterol and high fat diet. Apolipoprotein E (ApoE) deficient mice were divided into the following treatment groups: protonated NSAS 1.4% (w/w), untreated control and 2% (w/w) stigmastanol mixed with high-cholesterol/high-fat diet. Animals were treated for 12 weeks, blood samples were withdrawn every 4 weeks for determination of plasma cholesterol and triglyceride levels. At the end of the study the aortic roots were harvested for assessment of atherosclerotic lesions. NSAS at 1.4% (w/w) and stigmastanol at 2% (w/w) treatment groups showed significant decreases in plasma cholesterol concentrations at all time points relative to the control animals. The lesion sum area in 1.4% (w/w) NSAS and 2% (w/w) stigmastanol groups were significantly less from the control animals. In conclusion, in this study, the effectiveness of chronic administration of protonated NSAS material in the reduction of plasma cholesterol levels and decrease in development of atherosclerotic lesions was demonstrated in Apo-E deficient mice model.
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Project description:Dietary cholesterol supplements cause hypercholesterolemia and atherosclerosis along with a reduction of copper concentrations in the atherosclerotic wall in animal models. This study was to determine if target-specific copper delivery to the copper-deficient atherosclerotic wall can block the pathogenesis of atherosclerosis. Male New Zealand white rabbits, 10-weeks-old and averaged 2.0 kg, were fed a diet containing 1% (w/w) cholesterol or the same diet without cholesterol as control. Twelve weeks after the feeding, the animals were injected with copper-albumin microbubbles and subjected to ultrasound sonication specifically directed at the atherosclerotic lesions (Cu-MB-US) for target-specific copper delivery, twice a week for four weeks. This regiment was repeated 3 times with a gap of two weeks in between. Two weeks after the last treatment, the animals were harvested for analyses of serum and aortic pathological changes. Compared to controls, rabbits fed cholesterol-rich diet developed atherosclerotic lesion with a reduction in copper concentrations in the lesion tissue. Cu-MB-US treatment significantly increased copper concentrations in the lesion, and reduced the size of the lesion. Furthermore, copper repletion reduced the number of apoptotic cells as well as the content of cholesterol and phospholipids in the atherosclerotic lesion without a disturbance of the stability of the lesion. The results thus demonstrate that target-specific copper supplementation suppresses the progression of atherosclerosis at least in part through preventing endothelial cell death, thus reducing lipid infiltration in the atherosclerotic lesion.
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2023-12-08 | E-MTAB-12019 | biostudies-arrayexpress
Project description:BackgroundThe prostate cancer (PCa) diagnostic pathway is undergoing a radical change with the introduction of multiparametric magnetic resonance imaging (mpMRI), genomic testing, and different prostate biopsy techniques. It has been proposed that these tests should be used in a sequential manner to optimise risk stratification.ObjectiveTo characterise the genomic, epigenomic, and transcriptomic features of mpMRI-visible and -nonvisible PCa in clinically localised disease.Design, setting, and participantsMulticore analysis of fresh prostate tissue sampled immediately after radical prostatectomy was performed for intermediate- to high-risk PCa.InterventionLow-pass whole-genome, exome, methylation, and transcriptome profiling of patient tissue cores taken from microscopically benign and cancerous areas in the same prostate. Circulating free and germline DNA was assessed from the blood of five patients.Outcome measurement and statistical analysisCorrelations between preoperative mpMRI and genomic characteristics of tumour and benign prostate samples were assessed. Gene profiles for individual tumour cores were correlated with existing genomic classifiers currently used for prognostication.Results and limitationsA total of 43 prostate cores (22 tumour and 21 benign) were profiled from six whole prostate glands. Of the 22 tumour cores, 16 were tumours visible and six were tumours nonvisible on mpMRI. Intratumour genomic, epigenomic, and transcriptomic heterogeneity was found within mpMRI-visible lesions. This could potentially lead to misclassification of patients using signatures based on copy number or RNA expression. Moreover, three of the six cores obtained from mpMRI-nonvisible tumours harboured one or more genetic alterations commonly observed in metastatic castration-resistant PCa. No circulating free DNA alterations were found. Limitations include the small cohort size and lack of follow-up.ConclusionsOur study supports the continued use of systematic prostate sampling in addition to mpMRI, as avoidance of systematic biopsies in patients with negative mpMRI may mean that clinically significant tumours harbouring genetic alterations commonly seen in metastatic PCa are missed. Furthermore, there is inconsistency in individual genomics when genomic classifiers are applied.Patient summaryOur study shows that tumour heterogeneity within prostate tumours visible on multiparametric magnetic resonance imaging (mpMRI) can lead to misclassification of patients if only one core is used for genomic analysis. In addition, some cancers that were missed by mpMRI had genomic aberrations that are commonly seen in advanced metastatic prostate cancer. Avoiding biopsies in mpMRI-negative cases may mean that such potentially lethal cancers are missed.
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