The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies

Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures with circulating concentrations of IGFs (IGF‐I and IGF‐II) and IGFBPs (IGFBP‐1, IGFBP‐2 and IGFBP‐3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22–89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGF‐I, IGF‐II and IGFBP‐3. Higher body mass index was associated with lower concentrations of IGFBP‐1 and IGFBP‐2. Taller height was associated with higher concentrations of IGF‐I and IGFBP‐3 and lower concentrations of IGFBP‐1. Smokers had higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGFBP‐3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF‐II and lower concentrations of IGF‐I and IGFBP‐2. African Americans had lower concentrations of IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 and Hispanics had lower IGF‐I, IGF‐II and IGFBP‐3 than non‐Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk

A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk.

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness (P heterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease

Self-Consistent Single-Particle Simulation

Self{consistent single{particle Monte Carlo device simulations are presented. Self{ consistency is achieved by an iterative coupling{ scheme of single{particle frozen{ eld Monte Carlo simulations with solutions of the nonlinear Poisson equation. As an example a realistic 0.1 m n{MOSFET obtained from process simulation with maximum doping levels of about 2.5 10 is simulated. It is found that the resulting drain current is independent of the length of the time interval per iteration (provided that it is not too small) and independent of the density in the regions not visited by the particles taken either from a drift{ diusion or a hydrodynamic simulation. Therefore self{consistent single{particle Monte Carlo simulation is an accurate and robust simulation tool for the quasi{ballistic regime in sub 0.1 m MOSFETs. I

Receptor-associated Protein Interacts with Amyloid-β Peptide and Promotes Its Cellular Uptake*

Brain amyloid-β (Aβ) peptide accumulation and aggregation are critical events in the pathogenesis of Alzheimer disease. Increasing evidence has demonstrated that LRP1 is involved in Alzheimer disease pathogenesis. The physiological ligands of LRP1, including apoE, play significant roles in the cellular clearance of Aβ. The receptor-associated protein (RAP) is a specialized chaperone for members of the low density lipoprotein receptor family. RAP shares structural and receptor-binding properties with apoE. Here, we show that RAP binds to both Aβ40 and Aβ42 in a concentration-dependent manner and forms complexes with them. Fluorescence-activated cell sorter analysis showed that RAP significantly enhances the cellular internalization of Aβ in different cell types, including brain vascular smooth muscle, neuroblastoma, glioblastoma, and Chinese hamster ovary cells. This effect of RAP was confirmed by fluorescence microscopy and enzyme-linked immunosorbent assay. RAP binds to both LRP1 and heparin; however, the ability of RAP to enhance Aβ cellular uptake was blocked by heparin and heparinase treatment but not by LRP1 deficiency. Furthermore, the effects of RAP were significantly decreased in heparan sulfate proteoglycan-deficient Chinese hamster ovary cells. Our findings reveal that RAP is a novel Aβ-binding protein that promotes cellular internalization of Aβ

Efeito hipotensor de um extrato obtido da casca do fruto da Plinia peruviana (jabuticaba) em Rattus norvegicus

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2017.Doenças cardiovasculares são as principais causas de morte em todo o mundo. Dentre elas, a hipertensão arterial sistêmica também funciona como um dos principais fatores de risco para a ocorrência das demais e, embora existam diversos tratamentos, o número de casos não tratados ainda permanece grande. As plantas são bastante utilizadas na cultura popular para o tratamento de doenças e seus sintomas. Percebe-se a subutilização das cascas dos frutos da Plinia peruviana, conhecidos popularmente como jabuticaba, sendo que essas juntamente com as sementes chegam a representar 50% do fruto. Buscando a conservação e recuperação dos recursos presentes em plantas brasileiras, investigamos o efeito do extrato bruto hidroalcoólico da casca do fruto da Plinia peruviana sobre a pressão arterial de Rattus norvegicus. Desse modo, demonstramos que o tratamento por via oral com um extrato preparado a partir das cascas do fruto da Plinia peruviana (EPP) em ratas da linhagem SHR não apresenta nenhum efeito sobre a pressão arterial, a diurese, o ganho de peso ponderal ou os parâmetros bioquímicos e hematológicos. Entretanto, quando administrado por via intraduodenal, o EPP induz a queda da pressão arterial, tanto em machos como em fêmeas. Em situações de elevação dos níveis pressóricos, como a obtida através da infusão contínua de fenilefrina, o efeito hipotensor é maior, dependente da dose, e apresenta um efeito hipotensor de magnitude semelhante ao captopril (50 mg/Kg) para a dose de 300 mg/Kg. O efeito hipotensor do EPP foi bloqueado em parte pela infusão de L-NAME (7 mg/Kg/min), indicando o envolvimento do óxido nítrico nesse efeito. Entretanto, experimentos adicionais precisam ser realizados para caracterizar melhor a participação da enzima guanilato ciclase e dos canais de potássio (que podem ser ativados em cascata pelo óxido nítrico) no efeito do EPP. Frente a esses resultados, estudos pré-clínicos mais completos, assim como a avaliação da reprodutibilidade desses achados em humanos, são necessários para explorar de forma mais aprofundada o potencial de preparados obtidos a partir das cascas do fruto da jabuticabeira como nova possibilidade para o tratamento da hipertensão arterial.Abstract : Cardiovascular diseases are the leading cause of death in the world. Hypertension is one of the main risk factors for these diseases and in spite of the several available pharmacological treatments, uncontrolled high blood pressure remains a common clinical problem. Plants are widely used in folk medicine for the treatment of diseases and their symptoms. It is noticed the underutilization of the peels of the fruits of Plinia peruviana, popularly known in Brazil as ?jabuticaba?. In order to promote the conservation and recovery of the resources present in Brazilian plants, we have investigated the effect of the crude hydroalcoholic extract of the fruit peels of Plinia peruviana (EPP) on the blood pressure of Rattus norvegicus. In this way, we have shown that oral administration of EPP in female spontaneously hypertensive rats (SHR) had no effect on blood pressure, diuresis, weight gain, or biochemical and hematological parameters. However, when the extract was administered directly into the duodenum (intraduodenal route), it was able to drop blood pressure, without any differences between the effect recorded in male or female rats. Under phenylephrine-induced high blood pressure levels, the hypotensive effect generated by EPP was enhanced, presenting a dose-dependent profile and, at the dose of 300 mg/Kg, presenting a hypotensive effect similar to that obtained after captopril administration (50 mg/Kg). The EPP-induced hypotension was partially reduced in animals infused with L-NAME (7 mg/kg/min), indicating that nitric oxide plays a role in this effect. However, additional studies must be carried out to better investigate the involvement of both guanylate cyclase and potassium channels (which are targets in the downstream pathway of nitric oxide) in the cardiovascular effects of EPP. In order to explore the potential of preparations obtained from fruit peels of ?jabuticaba? for the treatment or prevention of human diseases, both additional pre-clinical and clinical evaluations are required to better characterize the effects reported in this study