Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer

Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins

Numerical analysis of different heating systems for warm sheet metal forming

The main goal of this study is to present an analysis of different heating methods frequently used in laboratory scale and in the industrial practice to heat blanks at warm temperatures. In this context, the blank can be heated inside the forming tools (internal method) or using a heating system (external method). In order to perform this analysis, a finite element model is firstly validated with the simulation of the direct resistance system used in a Gleeble testing machine. The predicted temperature was compared with the temperature distribution recorded experimentally and a good agreement was found. Afterwards, a finite element model is used to predict the temperature distribution in the blank during the heating process, when using different heating methods. The analysis also includes the evaluation of a cooling phase associated to the transport phase for the external heating methods. The results of this analysis show that neglecting the heating phase and a transport phase could lead to inaccuracies in the simulation of the forming phase.The authors gratefully acknowledge the financial support of the Portuguese Foundation for Science and Technology (FCT) under project PTDC/EMS-TEC/1805/2012 and by FEDER funds through the program COMPETE—Programa Operacional Factores de Competitividade, under the project CENTRO-07-0224-FEDER-002001 (MT4MOBI). The authors would like to thank Prof. A. Andrade-Campos for helpful contributions on the development of the finite element code presented in this work.info:eu-repo/semantics/publishedVersio

Etching a Fiber Post Surface with High-concentration Bleaching Agents

Introduction: Commonly, resin composites/cements fail to achieve proper bonding to fiber posts when their surfaces have not been previously etched. This study evaluated the effect of the concentration and application mode of hydrogen peroxide on the surface topography and bond strength of resin composite to glass-fiber posts. Methods and Materials: Fiber posts were immersed in 24% or 35% solutions (a high-concentration bleaching agent) of hydrogen peroxide (H2O2), or these solutions were applied over the post surface using a microbrush (n=10). Posts without any treatment were used as a control. After etching, the posts were silanated and an adhesive was applied. The posts were positioned in a mold, and a resin composite was incrementally inserted and light-cured. The post/resin assembly was serially sectioned into several beams that were subjected to a tensile bond strength test. The data were subjected to the two-way analysis of variance and Tukey test (α=0.05). The Dunnet's test was used to compare the experimental conditions to the control. The surface topography was analyzed using scanning electronic microscopy. Results: The non-etched post presented a relatively smooth surface without fiber exposure. Except for the application of 24% H2O2, the other experimental conditions increased the number of exposed fibers and bond strength in relation to the control. Although immersion resulted in higher values for the 24% H2O2 application, the mode of application did not alter bond strength when 35% H2O2 was used. Conclusions: The effect of the mode of application of H2O2 depended on its level of concentration. A high-concentration bleaching agent improved the bond strength of the resin composite to the post surface, regardless of which mode was used

Variations in strain affect friction and microstructure evolution in copper under a reciprocating tribological load

The microstructure of the materials constituting a metallic frictional contact strongly influences tribological performance. Being able to tailor friction and wear is challenging due to the complex microstructure evolution associated with tribological loading. Here, we investigate the effect of the strain distribution on these processes. High-purity copper plates were morphologically surface textured with two parallel rectangles—referred to as membranes—over the entire sample length by micro-milling. By keeping the width of these membranes constant and only varying their height, reciprocating tribological loading against sapphire discs resulted in different elastic and plastic strains. Finite element simulations were carried out to evaluate the strain distribution in the membranes. It was found that the maximum elastic strain increases with decreasing membrane stiffness. The coefficient of friction decreases with increasing membrane aspect ratio. By analyzing the microstructure and local crystallographic orientation, we found that both show less change with decreasing membrane stiffness

Metabolic Impact of Adult-Onset, Isolated, Growth Hormone Deficiency (AOiGHD) Due to Destruction of Pituitary Somatotropes

Growth hormone (GH) inhibits fat accumulation and promotes protein accretion, therefore the fall in GH observed with weight gain and normal aging may contribute to metabolic dysfunction. To directly test this hypothesis a novel mouse model of adult onset-isolated GH deficiency (AOiGHD) was generated by cross breeding rat GH promoter-driven Cre recombinase mice (Cre) with inducible diphtheria toxin receptor mice (iDTR) and treating adult Cre+/−,iDTR+/− offspring with DT to selectively destroy the somatotrope population of the anterior pituitary gland, leading to a reduction in circulating GH and IGF-I levels. DT-treated Cre−/−,iDTR+/− mice were used as GH-intact controls. AOiGHD improved whole body insulin sensitivity in both low-fat and high-fat fed mice. Consistent with improved insulin sensitivity, indirect calorimetry revealed AOiGHD mice preferentially utilized carbohydrates for energy metabolism, as compared to GH-intact controls. In high-fat, but not low-fat fed AOiGHD mice, fat mass increased, hepatic lipids decreased and glucose clearance and insulin output were impaired. These results suggest the age-related decline in GH helps to preserve systemic insulin sensitivity, and in the context of moderate caloric intake, prevents the deterioration in metabolic function. However, in the context of excess caloric intake, low GH leads to impaired insulin output, and thereby could contribute to the development of diabetes

Understanding the clinical spectrum of complicated Plasmodium vivax malaria: a systematic review on the contributions of the Brazilian literature

The resurgence of the malaria eradication agenda and the increasing number of severe manifestation reports has contributed to a renewed interested in the Plasmodium vivax infection. It is the most geographically widespread parasite causing human malaria, with around 2.85 billion people living under risk of infection. The Brazilian Amazon region reports more than 50% of the malaria cases in Latin America and since 1990 there is a marked predominance of this species, responsible for 85% of cases in 2009. However, only a few complicated cases of P. vivax have been reported from this region. A systematic review of the Brazilian indexed and non-indexed literature on complicated cases of vivax malaria was performed including published articles, masters' dissertations, doctoral theses and national congresses' abstracts. The following information was retrieved: patient characteristics (demographic, presence of co-morbidities and, whenever possible, associated genetic disorders); description of each major clinical manifestation. As a result, 27 articles, 28 abstracts from scientific events' annals and 13 theses/dissertations were found, only after 1987. Most of the reported information was described in small case series and case reports of patients from all the Amazonian states, and also in travellers from Brazilian non-endemic areas. The more relevant clinical complications were anaemia, thrombocytopaenia, jaundice and acute respiratory distress syndrome, present in all age groups, in addition to other more rare clinical pictures. Complications in pregnant women were also reported. Acute and chronic co-morbidities were frequent, however death was occasional. Clinical atypical cases of malaria are more frequent than published in the indexed literature, probably due to a publication bias. In the Brazilian Amazon (considered to be a low to moderate intensity area of transmission), clinical data are in accordance with the recent findings of severity described in diverse P. vivax endemic areas (especially anaemia in Southeast Asia), however in this region both children and adults are affected. Finally, gaps of knowledge and areas for future research are opportunely pointed out

Use of multidimensional item response theory methods for dementia prevalence prediction: an example using the Health and Retirement Survey and the Aging, Demographics, and Memory Study.

BACKGROUND: Data sparsity is a major limitation to estimating national and global dementia burden. Surveys with full diagnostic evaluations of dementia prevalence are prohibitively resource-intensive in many settings. However, validation samples from nationally representative surveys allow for the development of algorithms for the prediction of dementia prevalence nationally. METHODS: Using cognitive testing data and data on functional limitations from Wave A (2001-2003) of the ADAMS study (n = 744) and the 2000 wave of the HRS study (n = 6358) we estimated a two-dimensional item response theory model to calculate cognition and function scores for all individuals over 70. Based on diagnostic information from the formal clinical adjudication in ADAMS, we fit a logistic regression model for the classification of dementia status using cognition and function scores and applied this algorithm to the full HRS sample to calculate dementia prevalence by age and sex. RESULTS: Our algorithm had a cross-validated predictive accuracy of 88% (86-90), and an area under the curve of 0.97 (0.97-0.98) in ADAMS. Prevalence was higher in females than males and increased over age, with a prevalence of 4% (3-4) in individuals 70-79, 11% (9-12) in individuals 80-89 years old, and 28% (22-35) in those 90 and older. CONCLUSIONS: Our model had similar or better accuracy as compared to previously reviewed algorithms for the prediction of dementia prevalence in HRS, while utilizing more flexible methods. These methods could be more easily generalized and utilized to estimate dementia prevalence in other national surveys