Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 34
Filtrar
1.
Materials (Basel) ; 15(10)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35629751

RESUMO

Rapid tooling (RT) and additive manufacturing (AM) are currently being used in several parts of industry, particularly in the development of new products. The demand for timely deliveries of low-cost products in a variety of geometrical patterns is continuing to increase year by year. Increased demand for low-cost materials and tooling, including RT, is driving the demand for plastic and rubber products, along with engineering and product manufacturers. The development of AM and RT technologies has led to significant improvements in the technologies, especially in testing performance for newly developed products prior to the fabrication of hard tooling and low-volume production. On the other hand, the rapid heating cycle molding (RHCM) injection method can be implemented to overcome product surface defects generated by conventional injection molding (CIM), since the surface gloss of the parts is significantly improved, and surface marks such as flow marks and weld marks are eliminated. The most important RHCM technique is rapid heating and cooling of the cavity surface, which somewhat improves part quality while also maximizing production efficiencies. RT is not just about making molds quickly; it also improves molding productivity. Therefore, as RT can also be used to produce products with low-volume production, there is a good potential to explore RHCM in RT. This paper reviews the implementation of RHCM in the molding industry, which has been well established and undergone improvement on the basis of different heating technologies. Lastly, this review also introduces future research opportunities regarding the potential of RT in the RHCM technique.

2.
Nat Commun ; 12(1): 7037, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34857760

RESUMO

Growing evidence supports the importance of the p53 tumor suppressor in metabolism but the mechanisms underlying p53-mediated control of metabolism remain poorly understood. Here, we identify the multifunctional E4F1 protein as a key regulator of p53 metabolic functions in adipocytes. While E4F1 expression is upregulated during obesity, E4f1 inactivation in mouse adipose tissue results in a lean phenotype associated with insulin resistance and protection against induced obesity. Adipocytes lacking E4F1 activate a p53-dependent transcriptional program involved in lipid metabolism. The direct interaction between E4F1 and p53 and their co-recruitment to the Steaoryl-CoA Desaturase-1 locus play an important role to regulate monounsaturated fatty acids synthesis in adipocytes. Consistent with the role of this E4F1-p53-Steaoryl-CoA Desaturase-1 axis in adipocytes, p53 inactivation or diet complementation with oleate partly restore adiposity and improve insulin sensitivity in E4F1-deficient mice. Altogether, our findings identify a crosstalk between E4F1 and p53 in the control of lipid metabolism in adipocytes that is relevant to obesity and insulin resistance.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Obesidade/genética , Proteínas Repressoras/genética , Estearoil-CoA Dessaturase/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética , Adipócitos/patologia , Tecido Adiposo/patologia , Adulto , Idoso , Animais , Índice de Massa Corporal , Ácidos Graxos Monoinsaturados/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/patologia , Proteínas Repressoras/deficiência , Proteínas Repressoras/metabolismo , Transdução de Sinais , Estearoil-CoA Dessaturase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/metabolismo
3.
Cancer Res ; 81(19): 4981-4993, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34362796

RESUMO

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. SIGNIFICANCE: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.


Assuntos
Metabolismo dos Lipídeos , Lipidômica , Lipídeos de Membrana/metabolismo , Neoplasias da Próstata/metabolismo , Biomarcadores , Biologia Computacional/métodos , Metabolismo Energético , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipidômica/métodos , Masculino , Metabolômica/métodos , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/etiologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo
4.
Materials (Basel) ; 14(7)2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33916414

RESUMO

Achieving good quality of products from plastic injection moulding processes is very challenging, since the process comprises many affecting parameters. Common defects such as warpage are hard to avoid, and the defective parts will eventually go to waste, leading to unnecessary costs to the manufacturer. The use of recycled material from postindustrial waste has been studied by a few researchers. However, the application of an optimisation method by which to optimise processing parameters to mould parts using recycled materials remains lacking. In this study, Response Surface Methodology (RSM) and Particle Swarm Optimisation (PSO) methods were conducted on thick plate parts moulded using virgin and recycled low-density polyethylene (LDPE) materials (100:0, 70:30, 60:40 and 50:50; virgin to recycle material ratios) to find the optimal input parameters for each of the material ratios. Shrinkage in the x and y directions increased in correlation with the recycled ratio, compared to virgin material. Meanwhile, the tensile strength of the thick plate part continued to decrease when the recycled ratio increased. R30 (70:30) had the optimum shrinkage in the x direction with respect to R0 (100:0) material where the shrinkage increased by 24.49% (RSM) and 33.20% (PSO). On the other hand, the shrinkage in the y direction for R30 material increased by 4.48% (RSM) and decreased by 2.67% (PSO), while the tensile strength of R30 (70:30) material decreased by 0.51% (RSM) and 2.68% (PSO) as compared to R0 (100:0) material. Validation tests indicated that the optimal setting of processing parameter suggested by PSO and RSM for R0 (100:0), R30 (70:30), R40 (60:40) and R50 (50:50) was less than 10%.

5.
Materials (Basel) ; 14(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803313

RESUMO

Geopolymer concrete has the potential to replace ordinary Portland cement which can reduce carbon dioxide emission to the environment. The addition of different amounts of steel fibers, as well as different types of end-shape fibers, could alter the performance of geopolymer concrete. The source of aluminosilicate (fly ash) used in the production of geopolymer concrete may lead to a different result. This study focuses on the comparison between Malaysian fly ash geopolymer concrete with the addition of hooked steel fibers and geopolymer concrete with the addition of straight-end steel fibers to the physical and mechanical properties. Malaysian fly ash was first characterized by X-ray fluorescence (XRF) to identify the chemical composition. The sample of steel fiber reinforced geopolymer concrete was produced by mixing fly ash, alkali activators, aggregates, and specific amounts of hook or straight steel fibers. The steel fibers addition for both types of fibers are 0%, 0.5%, 1.0%, 1.5%, and 2.0% by volume percentage. The samples were cured at room temperature. The physical properties (slump, density, and water absorption) of reinforced geopolymer concrete were studied. Meanwhile, a mechanical performance which is compressive, as well as the flexural strength was studied. The results show that the pattern in physical properties of geopolymer concrete for both types of fibers addition is almost similar where the slump is decreased with density and water absorption is increased with the increasing amount of fibers addition. However, the addition of hook steel fiber to the geopolymer concrete produced a lower slump than the addition of straight steel fibers. Meanwhile, the addition of hook steel fiber to the geopolymer concrete shows a higher density and water absorption compared to the sample with the addition of straight steel fibers. However, the difference is not significant. Besides, samples with the addition of hook steel fibers give better performance for compressive and flexural strength compared to the samples with the addition of straight steel fibers where the highest is at 1.0% of fibers addition.

6.
Materials (Basel) ; 14(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669116

RESUMO

The primary motivation of developing ceramic materials using geopolymer method is to minimize the reliance on high sintering temperatures. The ultra-high molecular weight polyethylene (UHMWPE) was added as binder and reinforces the nepheline ceramics based geopolymer. The samples were sintered at 900 °C, 1000 °C, 1100 °C, and 1200 °C to elucidate the influence of sintering on the physical and microstructural properties. The results indicated that a maximum flexural strength of 92 MPa is attainable once the samples are used to be sintered at 1200 °C. It was also determined that the density, porosity, volumetric shrinkage, and water absorption of the samples also affected by the sintering due to the change of microstructure and crystallinity. The IR spectra reveal that the band at around 1400 cm-1 becomes weak, indicating that sodium carbonate decomposed and began to react with the silica and alumina released from gels to form nepheline phases. The sintering process influence in the development of the final microstructure thus improving the properties of the ceramic materials.

7.
Materials (Basel) ; 14(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673522

RESUMO

Aggregates can be categorized into natural and artificial aggregates. Preserving natural resources is crucial to ensuring the constant supply of natural aggregates. In order to preserve these natural resources, the production of artificial aggregates is beginning to gain the attention of researchers worldwide. One of the methods involves using geopolymer technology. On this basis, this current research focuses on the inter-particle effect on the properties of fly ash geopolymer aggregates with different molarities of sodium hydroxide (NaOH). The effects of synthesis parameters (6, 8, 10, 12, and 14 M) on the mechanical and microstructural properties of the fly ash geopolymer aggregate were studied. The fly ash geopolymer aggregate was palletized manually by using a hand to form a sphere-shaped aggregate where the ratio of NaOH/Na2SiO3 used was constant at 2.5. The results indicated that the NaOH molarity has a significant effect on the impact strength of a fly ash geopolymer aggregate. The highest aggregate impact value (AIV) was obtained for samples with 6 M NaOH molarity (26.95%), indicating the lowest strength among other molarities studied and the lowest density of 2150 kg/m3. The low concentration of sodium hydroxide in the alkali activator solution resulted in the dissolution of fly ash being limited; thus, the inter-particle volume cannot be fully filled by the precipitated gels.

8.
Materials (Basel) ; 14(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567696

RESUMO

This paper details analytical research results into a novel geopolymer concrete embedded with glass bubble as its thermal insulating material, fly ash as its precursor material, and a combination of sodium hydroxide (NaOH) and sodium silicate (Na2SiO3) as its alkaline activator to form a geopolymer system. The workability, density, compressive strength (per curing days), and water absorption of the sample loaded at 10% glass bubble (loading level determined to satisfy the minimum strength requirement of a load-bearing structure) were 70 mm, 2165 kg/m3, 52.58 MPa (28 days), 54.92 MPa (60 days), and 65.25 MPa (90 days), and 3.73 %, respectively. The thermal conductivity for geopolymer concrete decreased from 1.47 to 1.19 W/mK, while the thermal diffusivity decreased from 1.88 to 1.02 mm2/s due to increased specific heat from 0.96 to 1.73 MJ/m3K. The improved physicomechanical and thermal (insulating) properties resulting from embedding a glass bubble as an insulating material into geopolymer concrete resulted in a viable composite for use in the construction industry.

9.
Materials (Basel) ; 14(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567736

RESUMO

This current work focuses on the synthesis of geopolymer-based adsorbent which uses kaolin as a source material, mixed with alkali solution consisting of 10M NaOH and Na2SiO3 as well as aluminium powder as a foaming agent. The experimental range for the aluminium powder was between 0.6, 0.8, 1.0 and 1.2wt%. The structure, properties and characterization of the geopolymer were examined using X-Ray Diffraction (XRD), Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). Adsorption capacity and porosity were analysed based on various percentages of aluminium powder added. The results indicate that the use of aluminium powder exhibited a better pore size distribution and higher porosity, suggesting a better heavy metal removal. The maximum adsorption capacity of Cu2+ approached approximately 98%. The findings indicate that 0.8% aluminium powder was the optimal aluminium powder content for geopolymer adsorbent. The removal efficiency was affected by pH, adsorbent dosage and contact time. The optimum removal capacity of Cu2+ was obtained at pH 6 with 1.5 g geopolymer adsorbent and 4 h contact time. Therefore, it can be concluded that the increase in porosity increases the adsorption of Cu2+.

10.
Arch Toxicol ; 95(4): 1335-1347, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33585966

RESUMO

Mitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions. Despite these findings, there are currently limited models to assess the effect of mtDNA variation upon susceptibility to adverse drug reactions. Platelets offer a potential personalised model of this variation, as their anucleate nature offers a source of mtDNA without interference from the nuclear genome. This study, therefore, aimed to determine the effect of mtDNA variation upon mitochondrial function and drug-induced mitochondrial dysfunction in a platelet model. The mtDNA haplogroup of 383 healthy volunteers was determined using next-generation mtDNA sequencing (Illumina MiSeq). Subsequently, 30 of these volunteers from mitochondrial haplogroups H, J, T and U were recalled to donate fresh, whole blood from which platelets were isolated. Platelet mitochondrial function was tested at basal state and upon treatment with compounds associated with both mitochondrial dysfunction and adverse drug reactions, flutamide, 2-hydroxyflutamide and tolcapone (10-250 µM) using extracellular flux analysis. This study has demonstrated that freshly-isolated platelets are a practical, primary cell model, which is amenable to the study of drug-induced mitochondrial dysfunction. Specifically, platelets from donors of haplogroup J have been found to have increased susceptibility to the inhibition of complex I-driven respiration by 2-hydroxyflutamide. At a time when individual susceptibility to adverse drug reactions is not fully understood, this study provides evidence that inter-individual variation in mitochondrial genotype could be a factor in determining sensitivity to mitochondrial toxicants associated with costly adverse drug reactions.


Assuntos
Plaquetas/efeitos dos fármacos , DNA Mitocondrial/efeitos dos fármacos , Flutamida/análogos & derivados , Tolcapona/toxicidade , Adolescente , Adulto , DNA Mitocondrial/genética , Feminino , Flutamida/toxicidade , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Cancer Res ; 81(7): 1704-1718, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33547161

RESUMO

The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry-based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. SIGNIFICANCE: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.


Assuntos
Elongases de Ácidos Graxos/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , RNA Interferente Pequeno/uso terapêutico , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/fisiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Terapia de Alvo Molecular/métodos , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/farmacologia , Receptores Androgênicos/fisiologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Materials (Basel) ; 14(3)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535504

RESUMO

The mold-making industry is currently facing several challenges, including new competitors in the market as well as the increasing demand for a low volume of precision moldings. The purpose of this research is to appraise a new formulation of Metal Epoxy Composite (MEC) materials as a mold insert. The fabrication of mold inserts using MEC provided commercial opportunities and an alternative rapid tooling method for injection molding application. It is hypothesized that the addition of filler particles such as brass and copper powders would be able to further increase mold performance such as compression strength and thermal properties, which are essential in the production of plastic parts for the new product development. This study involved four phases, which are epoxy matrix design, material properties characterization, mold design, and finally the fabrication of the mold insert. Epoxy resins filled with brass (EB) and copper (EC) powders were mixed separately into 10 wt% until 30 wt% of the mass composition ratio. Control factors such as degassing time, curing temperature, and mixing time to increase physical and mechanical properties were optimized using the Response Surface Method (RSM). The study provided optimum parameters for mixing epoxy resin with fillers, where the degassing time was found to be the critical factor with 35.91%, followed by curing temperature with 3.53% and mixing time with 2.08%. The mold inserts were fabricated for EB and EC at 30 wt% based on the optimization outcome from RSM and statistical ANOVA results. It was also revealed that the EC mold insert offers better cycle time compared to EB mold insert material.

13.
Materials (Basel) ; 14(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374466

RESUMO

In recent years, research and development of geopolymers has gained significant interest in the fields of repairs and restoration. This paper investigates the application of a geopolymer as a repair material by implementation of high-calcium fly ash (FA) as a main precursor, activated by a sodium hydroxide and sodium silicate solution. Three methods of concrete substrate surface preparation were cast and patched: as-cast against ordinary Portland cement concrete (OPCC), with drilled holes, wire-brushed, and left as-cast against the OPCC grade 30. This study indicated that FA-based geopolymer repair materials (GRMs) possessed very high bonding strength at early stages and that the behavior was not affected significantly by high surface treatment roughness. In addition, the investigations using scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) spectroscopy have revealed that the geopolymer repair material became chemically bonded to the OPC concrete substrate, due to the formation of a C-A-S-H gel. Fundamentally, the geopolymer network is composed of tetrahedral anions (SiO4)4- and (AlO4)5- sharing the oxygen, which requires positive ions such as Na+, K+, Li+, Ca2+, Na+, Ba2+, NH4+, and H3O+. The availability of calcium hydroxide (Ca(OH)2) at the surface of the OPCC substrate, which was rich in calcium ions (Ca2+), reacted with the geopolymer; this compensated the electron vacancies of the framework cavities at the bonding zone between the GRM and the OPCC substrate.

14.
Pract Lab Med ; 21: e00174, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32613070

RESUMO

Matching of actionable tumor mutations with targeted therapy increases response rates and prolongs survival in lung cancer patients. Drug development and trials targeting genetic alterations are expanding rapidly. We describe the role of a Molecular Tumor Board (MTB) in the design of molecularly informed treatment strategies in our lung cancer patient population. Tumor DNA was sequenced using a 50-gene targeted next-generation sequencing panel. Cases were evaluated by a multidisciplinary MTB who suggested a course of treatment based on each patient's molecular findings. During a three-year period, 21 lung cancer patients were presented at the MTB. All patients lacked common activating EGFR mutations and ALK rearrangements. One patient had Stage IIIb disease; all others were Stage IV; 18 patients had received ≥1 prior line of therapy (range 0-5). Suggestions for treatment with a targeted therapy were made for 19/21 (90.5%) patients, and four patients (21%) underwent treatment with a targeted agent, two as part of a clinical trial. Identified barriers to treatment with targeted therapy included: ineligibility for clinical trials (n â€‹= â€‹2), lack of interest in study/distance to travel (n â€‹= â€‹2), lack of disease progression (n â€‹= â€‹2), poor performance status (n â€‹= â€‹5), decision to treat next with immunotherapy (n â€‹= â€‹3), and unknown (n â€‹= â€‹1). For the majority of lung cancer patients, the MTB provided recommendations based on tumor genetic profiles. Identified barriers to treatment suggest that presentation to the MTB at earlier stages of disease may increase the number of patients eligible for treatment with a genetically informed targeted agent.

15.
Clin Pharmacol Ther ; 108(6): 1195-1202, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32496628

RESUMO

Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89-4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10-3 . A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49-3.27, P = 6.30 × 10-9 ) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.


Assuntos
Angioedema/induzido quimicamente , Angioedema/genética , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Análise Mutacional de DNA , Fator V/genética , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma , Idoso , Angioedema/etnologia , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Exoma , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
16.
Toxicol Res (Camb) ; 9(2): 117-126, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32440343

RESUMO

The industrial solvent trichloroethylene (TCE) and its two major metabolites trichloroethanol (TCE-OH) and trichloroacetic acid (TCA) cause formic aciduria in male F344 rats. Prior treatment of male F344 rats with 1-aminobenzotriazole a cytochrome P450 inhibitor, followed by TCE (16mk/kg, po), completely prevented formic aciduria, but had no effect on formic acid excretion produced by TCA (8 or 16 mg/kg, po), suggesting TCA may be the proximate metabolite producing this response. Dow and Green reported an increase in the concentration of 5-methyltetrahydrofolate (5-MTHF) in the plasma of rats treated with TCE-OH, suggesting a block in the cycling of 5-MTHF to tetrahydrofolate (THF). This pathway is under the control of the vitamin B12-dependent methionine salvage pathway. We therefore treated rats with three daily doses of methylcobalamin (CH3Cbl) or hydroxocobalamin (OHCbl), a cofactor for methionine synthase, or L-methionine, followed by TCE (16 mg/kg) to determine if they could alleviate the formic aciduria. These pretreatments only partially reduced the excretion of formic acid in the urine. Although prior treatment with S-adenosyl-L-methionine had no effect on formic acid excretion. Consistent with these findings, the activity of methionine synthase in the liver of TCE-treated rats was not inhibited. Transcriptomic analysis of the liver-identified nine differential expressed genes, of note, was downregulation of Lmbrd1 involved in the conversion of vitamin B12 into CH3Cbl, a cofactor for methionine synthase. Our findings indicate that the formic aciduria produced by TCE-OH and TCA may be the result of a block in the recycling of 5-MTHF to THF, the effect on the methionine salvage pathway being a secondary response following acute exposure.

17.
Materials (Basel) ; 13(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32069829

RESUMO

Amorphous Fe- and Co-based alloys possess so-called soft magnetic properties. Due to the high sensitivity of the magnetisation vector to any inhomogeneities occurring in these alloys, it is possible to assess indirectly structural defects. This paper presents the results of research on the structure and magnetic properties of bulk amorphous alloys with a high content of Fe and Co. The magnetic properties of the produced alloys were tested using a Faraday magnetic balance and a vibrating sample magnetometer (VSM). Analysis of the magnetisation process in the region known as the approach to ferromagnetic saturation was carried out in accordance with Kronmüller's theorem. Magnetisation in magnetic fields of greater than the effective anisotropy field (Holstein-Primakoff para-process) was also studied. For the studied alloys, it was found that an increase in Fe content causesan increase in saturation magnetisation, and decreases in the values of the coercive field and thespin-wave stiffness parameter, Dspf. A relationship was observed between the width of the amorphous halo and the value of the coercive field. However, no significant links were found between either the presence of structural defects and the properties of these materials, or between the Co content and the value of the coercive field.

18.
J Lipid Res ; 61(2): 205-218, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31806729

RESUMO

We previously described the expression of CD36 and LPL by breast cancer (BC) cells and tissues and the growth-promoting effect of VLDL observed only in the presence of LPL. We now report a model in which LPL is bound to a heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to internalize VLDLs via receptor-mediated endocytosis. We also demonstrate that gene-expression programs for lipid synthesis versus uptake respond robustly to triglyceride-rich lipoprotein availability. The literature emphasizes de novo FA synthesis and exogenous free FA uptake using CD36 as paramount mechanisms for lipid acquisition by cancer cells. We find that the uptake of intact lipoproteins is also an important mechanism for lipid acquisition and that the relative reliance on lipid synthesis versus uptake varies among BC cell lines and in response to VLDL availability. This metabolic plasticity has important implications for the development of therapies aimed at the lipid dependence of many types of cancer, in that the inhibition of FA synthesis may elicit compensatory upregulation of lipid uptake. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology.-.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Endocitose , Gotículas Lipídicas/metabolismo , Lipoproteínas VLDL/metabolismo , Humanos , Células Tumorais Cultivadas
19.
Nat Commun ; 10(1): 3288, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337761

RESUMO

Recent years have seen an increase of extracellular vesicle (EV) research geared towards biological understanding, diagnostics and therapy. However, EV data interpretation remains challenging owing to complexity of biofluids and technical variation introduced during sample preparation and analysis. To understand and mitigate these limitations, we generated trackable recombinant EV (rEV) as a biological reference material. Employing complementary characterization methods, we demonstrate that rEV are stable and bear physical and biochemical traits characteristic of sample EV. Furthermore, rEV can be quantified using fluorescence-, RNA- and protein-based technologies available in routine laboratories. Spiking rEV in biofluids allows recovery efficiencies of commonly implemented EV separation methods to be identified, intra-method and inter-user variability induced by sample handling to be defined, and to normalize and improve sensitivity of EV enumerations. We anticipate that rEV will aid EV-based sample preparation and analysis, data normalization, method development and instrument calibration in various research and biomedical applications.


Assuntos
Vesículas Extracelulares/química , Padrões de Referência , Biomarcadores , Pesquisa Biomédica/métodos , Meios de Cultivo Condicionados , Células HEK293 , Humanos
20.
PLoS One ; 14(6): e0218115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242253

RESUMO

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Músculo Esquelético , Rabdomiólise , Sequenciamento Completo do Genoma , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Rabdomiólise/induzido quimicamente , Rabdomiólise/genética , Rabdomiólise/metabolismo , Rabdomiólise/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...