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Background: Abnormal thyroid hormone (TH) metabolism is significantly associated with impaired left ventricular (LV) function and death. Although THwas traditionally thought to be produced exclusively by the thyroid gland, an increasing number of studies report TH production in other tissues. Based on these findings, we evaluated whether the genes required for TH biosynthesis are expressed in the human heart, and whether their expression is altered in patients with ischemic cardiomyopathy (ICM) and is related to epigenetic variations. Methods: Twenty-three LV tissue sampleswere obtained fromICMpatients (n=13) undergoing heart transplantation and control donors (n=10) for RNA sequencing analysis. We increased the LV samples to 27 for the ELISA determination of total T4 and T3 tissue levels. For epigenomic studies, 850 K InfiniumMethylationEPIC BeadChip platform was performed. Results: Using RNA-sequencing, we displayed the expression levels of all components required for TH biosynthesis in human heart tissue. We observed significantly altered expression of genes encoding thyroperoxidase (TPO; -2.48-fold, P < 0.05) and dual oxidase 2 (2.83-fold, P < 0.05), themain enzymatic systemof TH production, and significant relationships between their altered expression and LV remodeling parameters. In addition, epigenetic analysis revealed a differential methylation pattern in TPO, and triiodothyronine tissue levels were significantly decreased (P < 0.01). Conclusions: These results showed that the human heart expresses the TH biosynthesismachinery, being altered its main enzymatic system in patients with ICM. Given the relevance of TH in cardiac pathology, our results provide a foundation for new therapeutic approaches based on TPO for treating ICM. (C) 2017 Published by Elsevier Ireland Ltd.

Producción Científica, Microwave assisted extraction has been proved to be a useful tool for the recovery of valuable compounds from natural products. However, little is known about the dielectric properties for mixtures of natural products and solvents. In this work, a semi-empirical model is proposed to calculate the dielectric properties of these systems. The variables considered were temperature, solvent composition and solid-liquid ratio. Grape pomace was used as the solid matrix and ethanol-water mixtures as the solvent. The experimental dielectric constant and loss factor of these multiphase solid-solvent samples were measured and compared to the proposed model. Loss factor values were taken under special consideration, since they were boosted by the release of ions from the solid (an increase between 9 and 83%). The model proposed here reproduces the dielectric properties of this multiphase media with an average deviation of 8.1% for the dielectric constant and of 24.8% for the loss factor., Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA330U13)

Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)–derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo. Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas. Significance: Our findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38–53. ©2016 AACR. See related commentary by Höpken, p. 14. This article is highlighted in the In This Issue feature, p. 1

BACKGROUND: The detection of heart transplant rejection by non-invasive methods remains a major challenge. Despite the well-known importance of the study of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) in the heart, its role as a rejection marker has never been analyzed. Our objective in this study was to determine whether circulating SERCA2a could be a good marker of cardiac rejection. METHODS: We collected 127 consecutive endomyocardial biopsies (EMBs) and serum samples from adult heart transplant recipients (49 without allograft rejection and 78 with the diagnosis of biopsy allograft rejection, including 48 Grade 1R, 21 Grade 2R and 9 Grade 3R). Serum concentrations of SERCA2a were determined using a specific sandwich enzyme-linked immunosorbent assay. We also analyzed SERCA2a expression changes on EMBs using immunofluorescence. RESULTS: SERCA2a cardiac tissue and serum levels were decreased in patients with cardiac rejection (p < 0.0001). A receiver-operating characteristic analysis showed that SERCA2a strongly discriminated between patients with and without allograft rejection: normal grafts vs all rejecting grafts (AUC = 0.804); normal grafts vs Grade 1R (AUC = 0.751); normal grafts vs Grade 2R (AUC = 0.875); normal grafts vs Grade 3R (AUC = 0.922); normal grafts vs Grade 2R and 3R (AUC = 0.889), with p < 0.0001 for all comparisons. CONCLUSIONS: We demonstrated that changes in SERCA2a cardiac tissue and serum levels occur in cardiac allograft rejection. Our findings suggest that SERCA2a concentration assessment may be a relatively simple, non-invasive test for heart transplant rejection, showing a strong capability for detection that improves progressively as rejection grades increase. (C) 2017 The Authors. Published by Elsevier Inc.

Producción Científica, Microwave assisted extraction advantages are widely recognised. However, its implementa-tion at industrial scale is restricted due to microwave limitations. In this work, a microwavepretreatment is proposed as an easy scale-up alternative for grape pomace polyphenolextraction, especially for anthocyanins. The double effect of this pretreatment on extractionyield and on product richness is assessed. Microwaves accelerate the extraction kineticsof most compounds, but their effect on polyphenols is more pronounced than in othersubstances (like sugars and fibres). These differentiated rates are exploited to improve thepolyphenol richness of the final dry product. By selecting the appropriate operating condi-tions, polyphenol yield was increased by 57% and, simultaneously, dry product richness wasenhanced by 32%. Also, anthocyanin extraction boost was remarkable. Its content in the finaldry product was 85% higher than the one obtained without the microwave pretreatment.The cellular bioactivity of these extracts was improved by 83% and 133%.

Both bird and mixed vertebrate–insect (MVI) pollination systems are very rare in Europe and the Mediterranean region. Because MVI can ensure reproduction over a wider range of environmental conditions than when insects are the sole pollinators, under certain circumstances such systems are highly advantageous to plants. Here, we investigated the pollination and some reproductive traits of the Tyrrhenian Scrophularia trifoliata, the only species of the genus possessing two showy dark spots inside the corolla, for which MVI pollination system had been inferred on the basis of limited censuses. We conducted field experiments to study MVI pollination and some reproductive traits and elucidate the role of corolla spots, analysing their ultraviolet pattern, histology and pigments vs the rest of the corolla. The primary pollinators were wasps and passerine birds. Corolla spots absorb UV light, present abundance of anthocyanins and are histologically identical to the rest of the corolla. Control flowers had higher visitation frequency than flowers without spots. S. trifoliata is self-compatible with efficient intrafloral protogyny and herkogamy that prevent self-pollination but not geitonogamy. We confirmed the existence of a mixed bird–insect pollination system in S. trifoliata. This system is found in three other Scrophularia species with large, showy flowers—two Mediterranean (S. grandiflora and S. sambucifolia) and one Macaronesian (S. calliantha). Unlike those species, S. trifoliata has two large spots inside the corolla. These likely operate as nectar guides and their dark coloration is related to abundant anthocyanin content. This article is protected by copyright. All rights reserved.

An essential factor for the production of nitric oxide by nitric oxide synthase 1 (NOS1), major modulator of cardiac function, is the cofactor tetrahydrobiopterin (BH4). BH4 is regulated by GTP cyclohydrolase 1, the rate-limiting enzyme in BH4 biosynthesis which catalyses the formation of dihydroneopterin 3′triphosfate from GTP, producing BH4 after two further steps catalyzed by 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. However, there are other essential factors involved in the regulation of NOS1 activity, such as protein inhibitor of NOS1 (PIN), calmodulin, heat shock protein 90 and NOS interacting protein. All these molecules have never been analysed in human non-ischemic dilated hearts (DCM). In this study we demonstrated that the upregulation of cardiac NOS1 is not accompanied by increased NOS1 activity in DCM, partly due to the elevated PIN levels and not because of alterations in biopterin biosynthesis. Notably, the PIN concentration was significantly associated with impaired ventricular function, highlighting the importance of this NOS1 activity inhibitor in Ca2+ homeostasis. These results take a central role in the current list of targets for future studies focused on the complex cardiac dysfunction processes through more efficient harnessing of NOS1 signalling.

The role of nitric oxide synthase 1 (NOS1) as a major modulator of cardiac function has been extensively studied in experimental models; however, its role in human ischemic cardiomyopathy (ICM) has never been analysed. Thus, the objectives of this work are to study NOS1 and NOS-related counterparts involved in regulating physiological function of myocyte, to analyze NOS1 localisation, activity, dimerisation, and its relationship with systolic function in ICM. The study has been carried out on left ventricular tissue obtained from explanted human hearts. Here we demonstrate that the upregulation of cardiac NOS1 is not accompanied by an increase in NOS activity, due in part to the alterations found in molecules involved in the regulation of its activity. We observed partial translocation of NOS1 to the sarcolemma in ischemic hearts, and a direct relationship between its protein levels and systolic ventricular function. Our findings indicate that NOS1 may be significant in the pathophysiology of human ischemic heart disease with a preservative role in maintaining myocardial homeostasis.

Several hypotheses have been proposed to explain the pattern of pollinator visits to vertical inflorescences. These range from a response to a pattern of resources to merely instinctive behaviour. In dichogamous plants, such behaviour has been associated with promoting outcrossing and avoiding geitonogamy. We here analyse behaviour of the principal pollinator groups in five protogynous species of Scrophularia with different flower sizes (S. sambucifolia, S. grandiflora, S. lyrata, S. scorodonia and S. canina), and the distribution of sexual phases along the inflorescences. The results in all cases show that pollinators follow a pattern of ascending visits accompanied by movements between flowers of the same whorl (horizontal movements). The relative frequency of these horizontal movements depends on the flower size, with a higher frequency in species with large flowers. In vertical movements of the three more common pollinator groups to several plant species (bumblebees, wasps and small bees), the behaviour was essentially independent of flower size, with bumblebees having the highest ratio of ascents to descents. Behaviour of the pollinators, together with the absence of a definite pattern of distribution of the sexual phases along the inflorescence, implies that geitonogamy is not avoided in any of the Scrophularia species studied.

13 páginas, 7 figuras, 7 figuras suplementarias, 7 tablas suplementarias.-- et al., Aging in worms and flies is regulated by the PI3K/Akt/Foxo pathway. Here we extend this paradigm to mammals. Ptentg mice carrying additional genomic copies of Pten are protected from cancer and present a significant extension of life span that is independent of their lower cancer incidence. Interestingly, Ptentg mice have an increased energy expenditure and protection from metabolic pathologies. The brown adipose tissue (BAT) of Ptentg mice is hyperactive and presents high levels of the uncoupling protein Ucp1, which we show is a target of Foxo1. Importantly, a synthetic PI3K inhibitor also increases energy expenditure and hyperactivates the BAT in mice. These effects can be recapitulated in isolated brown adipocytes and, moreover, implants of Ptentg fibroblasts programmed with Prdm16 and Cebpβ form subcutaneous brown adipose pads more efficiently than wild-type fibroblasts. These observations uncover a role of Pten in promoting energy expenditure, thus decreasing nutrient storage and its associated damage, Work in the laboratory of A.M.V. was funded by grant SAF2009-08114 and by the CIBERDEM (ISCIII), and work in the laboratory of E. Rial was funded by grants SAF2010-20256 and Consolider-Ingenio CSD2007-00020. A.O.-M. was recipient of a predoctoral contract of the Regional Government of Madrid. E.L.-G. was recipient of a predoctoral contract from the Spanish Ministry of Education. M.M.G.-B. was supported by the “Ramon y Cajal” program of the Spanish Ministry of Science and Innovation.

doi: 10.1111/j.1741-2358.2012.00626.x Evaluation of the efficacy of two mouthrinses formulated for the relief of xerostomia of diverse origin in adult subjects Objective: To evaluate the efficacy of two new mouthrinses in the reduction of xerostomia-associated symptomatology. Background: Xerostomia is a common chronic health condition that affects a great number of adults and significantly deteriorates quality of life, such that treatment is necessary. Materials and methods: Sixty-seven adult subjects of both sexes presenting xerostomia of diverse origin were selected. Mouthrinses were tested using a double-blind, randomized, cross-over clinical trial with an intervining wash out period. Results: The 100% of subjects presented sensation of dry mouth, and 86% stated sensation of thick saliva. Burning tongue sensation, need to drink liquids to swallow and the sensation of swallowing difficulty were recorded in more than 50% of the patients. The most frequent pathologies in the sample were depression, arthritis, and arterial hypertension. Results of the clinical tests showed that mouthrinse 1 relieves sensation of dry mouth, need to drink liquids, and swallowing difficulty. In contrast, mouthrinse 2 relieves only latter two symptoms. Both rinses were more effective in relieving xerostomia-associated symptomatology in patients taking 3 or more medicines simultaneously. Conclusion: Both mouthrinses were effective in relieving various xerostomia symptoms, could be distributed at a low cost, thereby improving the quality of life of population affected.

Introduction: Some studies report that atopic patients have a greater frequency of delayed-type sensitization than non-atopic patients. Objective: To determine the influence of the atopic condition on delayed sensitization to dental materials. Design: cross-sectional study. Methods: Forty (40) atopic subjects and forty (40) non-atopic subjects, of both sexes, between 20 and 65 years of age were included. The determination of delayed sensitization to dental materials was performed using patch test. An oral exam was also carried out to check for lesions of the oral mucosa. Results: 61.25% of the patients were positive for delayed-type sensitization to one or more allergens, being palladium chloride (21.25%), ammoniated mercury (20%), benzoyl peroxide (12.5%) and amalgam (10%) the most frequent. The frequency of sensitization was 67.5% in the group of atopic patients, compared to 55% in the non atopic group (p>0.05). The materials with the greatest difference of sensitization in atopic compared to non-atopic patients were ammoniated mercury, benzoyl peroxide, amalgam and Bisphenol A Dimethacrylate (BIS-GMA). Conclusion: The atopic condition is not related to a higher frequency of delayed sensitization to a battery of dental materials. Key words: Patch test, delayed-type sensitization, allergy contact, atopia, dental materials.

We investigated the role of resource limitation, ovary reserve, and selective abortion in controlling flower and fruit set in the Mediterranean leguminous shrub Anagyris foetida. The removal of bracts, but not that of leaves, reduced the initiation of fruit with respect to controls. The removal of a large proportion (2/3 of the total) of preanthesic inflorescences increased the reproductive capacity of individuals via two different strategies: (1) maintaining the number of fruit-bearing inflorescences, but increasing the number of fruits per inflorescence and seeds per fruit; and (2) increasing the number of fruit-bearing inflorescences, while maintaining fruits/inflorescence and seeds/fruit ratios unchanged. At the level of the inflorescence, most of the ripe fruits were located on the basalmost whorls of the raceme. Within the legume, fertilization was independent of the position of ovules, although the more basal presented lower rates of fertilization than the more central-stylar. The same was...

† Background and Aims It has traditionally been considered that the flowers of Scrophularia are mainly pollinated by wasps. We studied the pollination system of four species which stand out for their large and showy flowers: S. sambucifolia and S. grandiflora (endemics of the western Mediterranean region), S. trifoliata (an endemic of the Tyrrhenian islands) and S. calliantha (an endemic of the Canary Islands). Our principal aim was to test whether these species were pollinated by birds or showed a mixed pollination system between insects and birds. † Methods Censuses and captures of insects and birds were performed to obtain pollen load transported and deposited on the stigmas. Also, a qualitative and quantitative analysis of the flowers and inflorescences was carried out. † Key Results Flowers were visited by Hymenoptera and by passerine birds. The Canarian species was the most visited by birds, especially by Phylloscopus canariensis, and its flowers were also accessed by juveniles of the lizard Gallotia stehlini. The most important birds in the other three species were Sylvia melanocephala and S. atricapilla. The most important insect-functional groups in the mixed pollination system were: honey-bees and wasps in S. sambucifolia; bumble-bees and wasps in S. grandiflora; wasps in S. trifoliata; and a small bee in S. calliantha. † Conclusions The species studied show a mixed pollination system between insects and passerine birds. In S. calliantha there is, in addition, a third agent ( juveniles of Gallotia stehlini). The participation of birds in this mixed pollination system presents varying degrees of importance because, while in S. calliantha they are the main pollinators, in the other species they interact to complement the insects which are the main pollinators. A review of different florae showed that the large showy floral morphotypes of Scrophularia are concentrated in the western and central Mediterranean region, Macaronesia and USA (New Mexico).

Background. Several European governments have recently mandated price cuts in drugs to reduce health care spending. However, such measures without supportive evidence may compromise patient care because manufacturers may withdraw current products or not launch new agents. A value-based pricing scheme may be a better approach for determining a fair drug price and may be a medium for negotiations between the key stakeholders. To demonstrate this approach, pharmacoeconomic (PE) modeling was used from the Spanish health care system perspective to estimate a value-based price for bevacizumab, a drug that provides a 1.4-month survival benefit to patients with metastatic colorectal cancer (mCRC). The threshold used for economic value was three times the Spanish per capita GDP, as recommended by the World Health Organization (WHO). Methods. A PE model was developed to simulate outcomes in mCRC patients receiving chemotherapy ± bevacizumab. Clinical data were obtained from randomized trials and costs from a Spanish hospital. Utility estimates were determined by interviewing 24 Spanish oncology nurses and pharmacists. A price per dose of bevacizumab was then estimated using a target threshold of €78,300 per quality-adjusted life year gained, which is three times the Spanish per capita GDP. Results. For a 1.4-month survival benefit, a price of €342 per dose would be considered cost effective from the Spanish public health care perspective. The price may be increased to €733 or €843 per dose if the drug were able to improve patient quality of life or enhance survival from 1.4 to 3 months. Conclusions. This study demonstrated that a value-based pricing approach using PE modeling and the WHO criteria for economic value is feasible and perhaps a better alternative to government mandated price cuts. The former approach would be a good starting point for opening dialog between European government payers and the pharmaceutical industry.

Amelogenesis imperfecta is a group of genetic conditions that affect the structure and clinical appearance of tooth enamel. The types (hypoplastic, hypocalcified, and hypomature) are correlated with defects in different stages of the process of enamel synthesis. Autosomal dominant, recessive, and X-linked types have been previously described. These disorders are considered clinically and genetically heterogeneous in etiology, involving a variety of genes, such as AMELX, ENAM, DLX3, FAM83H, MMP-20, KLK4, and WDR72. The mutations identified within these causal genes explain less than half of all cases of amelogenesis imperfecta. Most of the candidate and causal genes currently identified encode proteins involved in enamel synthesis. We think it is necessary to refocus the search for candidate genes using biochemical processes. This review provides theoretical evidence that the human SLC4A4 gene (sodium bicarbonate cotransporter) may be a new candidate gene.

Titania nanotubes grown on titanium through the electrochemical anodization are an attractive nanostructure due to their applicability in areas such as photocatalysis, dye-sensitized solar cells, sensors, etc. Nanotubes functionalization with nanoparticles or different molecules is becoming a common practice that can either aid or enhance their performance in a variety of applications. Dyes have been used in solar cells and photocatalysis to sensitize the semiconductor and, biological dyes such as anthocyanins have been tested for these purposes due to their low cost and environmentally friendly nature (1). In this work, titania nanotubes electrodes were functionalized with anthocyanins in order to test their performance as sensitizers for photoelectrocatalytic purposes. Anthocyanins alcoholic extract has been obtained from hibiscus flower (Hibiscus sabdariffa L) and immobilized on titania nanotubes (TiO2 Nts ) grown from 2 cm2 titania plates (TiO2 Nts/Ti) by anodization at 30 V in a glycerol:water (2:1) solution containing sodium fluoride and sodium sulfate. Anthocyanins immobilization was achieved through immersion for 48 h of the TiO2/Ti plates in the alcoholic extract at O°C. The antioxidant activity from both, the as-extracted and the immobilized, anthocyanins was tested by the ABTS assay. This essay showed that a 1:100 dilution from the extract had an antioxidant activity of 550 μTrolox while the immobilized anthocyanins had a higher antioxidant activity of 699 μTrolox (2). Electrochemical techniques have gained importance in the study of nanostructured materials especially in the field of surface characterization. Within this work, cyclic voltammetry was used to determine surface characteristics from the bare TiO2 nanotubes and from the nanotubes functionalized with anthocyanins. Through cyclic voltammetry in a pH 7.00 1.0 M buffer phosphate it was possible to confirm TiO2 Nts functionalization with anthocyanins as it can be seen from the change in the voltamperogram´s shape for the bare nanotubes and after functionalization with anthocyanins (Figure 1). Cyclic voltammetry on anthocyanins-TiO2-Nts electrode showed two oxidation peaks at -0.390 V and -0.096 V (vs. mercurous sulfate electrode) which can be attributed to the delphinidin-3-O-glucoside (3), the main anthocyanin found in Hibiscus sabdariffa L (4). Complementary results concerning these electrodes performance will be presented at the conference. References Zyoud, A., Zaatar, N., Saadeddin, I., Helal, M.H., Campet, G., Hakim, M., Park, D., Hilal, H. 2011. Alternative natural dyes in water purification: Anthocyanin as TiO2-sensitizer in methyl orange photo-degradation. Solid State Sciences, 13: 1268-1275. Pérez‐Jiménez, J., & Saura‐Calixto, F. (2008). Anti‐oxidant capacity of dietary polyphenols determined by ABTS assay: a kinetic expression of the results. International journal of food science & technology, 43(1), 185-191. Janeiro, P., Oliveira-Brett, A. M. 2007. Redox behavior of anthocyanins present in Vitis vinifera L. Electroanalysis. 19(17): 1779-1786. Galicia-Flores, L. A., Salinas-Moreno, Y., Espinoza- García, B. M. y Sánchez-Feria, C. 2008. Caracterización fisicoquímica y actividad antioxidante de extractos de jamaica (Hibiscus sabdariffa L) nacional e importada. Revista Chapingo Serie Horticultura. 14(2):121-129. Figure 1

Objective: This study compared the cost-effectiveness of ranibizumab with that of photodynamic therapy (PDT) in the treatment of predominantly classic choroidal neovascularization secondary to age-related macular degeneration (AMD) from the perspective of a third-party payer in a Spanish setting. Methods: We constructed a Markov model with 5 states defined by visual acuity (VA) in the better-seeing eye (Snellen scale), as follows: VA >20/40, ≤20/40 to >20/80, ≤20/80 to >20/200, ≤20/200 to >20/400, and ≤20/400. A death state was also included. We took transition probabilities, number of ranibizumab injections, and number of PDT treatments from the ANCHOR (Anti—Vascular Endothelial Growth Factor Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration) trial. Utilities were taken from a published study of patients' preferences. We used unit costs from our hospital and drug costs from a national database. Resource utilization was determined by an ophthalmologist according to current clinical practice. We performed univariate, threshold, and probabilistic sensitivity analyses. Incremental costs (2007 €) and quality-adjusted life-years (QALYs), both discounted at a 3% annual rate, and incremental cost-effectiveness ratios (ICERs; €/QALY) were determined for the 2-year and life-expectancy time horizons. Results: Treating patients with varying degrees of visual impairment with ranibizumab instead of PDT, with a 2-year time horizon, was found to be €18,328 more costly and to confer 0.140 additional QALY (€131,275/QALY). This ICER was reduced to €39,398/ QALY for the longer life-expectancy time horizon. According to the probabilistic sensitivity analysis, PDT is the therapy of choice in all cases below the threshold of €30,000/QALY for the 2-year time horizon. Ranibizumab was the optimal intervention in 26% of cases in the longer lifetime horizon. When the initial VA was ≤20/400, the ICER increased to €255,477 over 2 years. When ranibizumab was administered on an as-needed basis, as in the PrONTO (Prospective Optical coherence tomography imaging of patients with Neovascular AMD Treated with intra-Ocular ranibizumab) trial, the ICERs were reduced to €29,566/QALY and €11,469/QALY in the 2-year and life-expectancy horizons, respectively. Conclusions: Based on these results, ranibizumab was not cost-effective when administered on a monthly basis. When administered as needed, ranibizumab was cost-effective compared with PDT for the treatment of AMD.

In Anagyris foetida, the fruits are disseminated by fall under gravity. No dispersing agent is as yet known, so that the fruits are located near the mother plant. The species presents an important seed bank that differs between the two populations studied, probably due to their different production of seeds/individual and to the livestock pressure. The germination of control seeds was found to be null or very low, with no improvement following exposure to high temperatures, but reaching high values following scarification in all the populations studied. This indicates that the failure in germination must be attributed to the hardness of the testa, with the seeds presenting physical dormancy. Also, the browsing of sheep on ripe fruit increases germination to 48% due to mechanical scarification, with this being the only positive effect those animals have on these plants. There were differences in germination after scarification between populations and years which could have been due to intrinsic characteristics.

As most plants of the Mediterranean region bloom in spring, there have been few studies of the reproductive biology of species with autumn–winter flowering. In this study, we investigate the breeding system of Anagyris foetida, one of the few shrubs that blooms at this time. The floral, phenological, and reproductive aspects of two populations of this Mediterranean legume from south-west Spain were studied via field and laboratory experiments. The variability of fruit and seeds was studied in another 12 Iberian populations with respect to certain meteorological parameters (temperature and rainfall). Anagyris foetida shows cauliflory, marked floral longevity, and adichogamy. The peak of flowering is in January–February. It is self-compatible, with no clear advantage of cross- over self-pollination, and with virtually no autonomous self-pollination. This is because the stigma, like some other legumes, prevents the germination of pollen if its surface is not ruptured by pollinators. The number of seeds per fruit under natural pollination was positively correlated with the total rainfall during the fruiting period (from January to May), and significantly influenced the percentage of fruit weight represented by the pericarp, in the sense that the smaller the number of viable seeds in the fruit, the greater the percentage of pericarp weight. © 2008 The Linnean Society of London, Botanical Journal of the Linnean Society, 2008, 157, 519–532.

BACKGROUND: Grape skin cell walls form a barrier against the diffusion of colour. The colour of red wines is mainly due to anthocyanins, although their concentration in wine is not always correlated with the anthocyanin content of grape skins. The cell wall composition changes during fruit ripening, so it was thought that a study of the ripening behaviour of four premium varieties might provide information on how the composition changes during ripening and explain the technological differences. RESULTS: The largest quantities of skin cell wall material (CWM) were isolated from Monastrell grapes, probably owing to the greater number of cell layers they contain and the thicker cell walls. During ripening, a loss of skin CWM (e.g. 120–60 and 65–45 mg CWM g−1 fresh skin for Monastrell J and Cabernet Sauvignon respectively) and galactose (e.g. 36–20 and 55–30 mg g−1 CWM for Cabernet Sauvignon and Monastrell J respectively) was observed, together with a decrease in the degree of pectin methylation and acetylation, except in Syrah, in which pectin methylation remained unchanged. These changes were accompanied by the accumulation of glucose, while other neutral sugars showed no significant variations. A correlation was found between the degree of ripening and those constituents changing in the grape skin cell wall. CONCLUSION: The cell wall composition differs sufficiently between grape varieties to allow discrimination between them. Ripening was associated with a decrease in the quantity of CWM and galactose in the cell walls. Monastrell showed the largest quantities of both throughout ripening. The differences observed between Monastrell and the other varieties would explain the technological differences between them. Copyright © 2007 Society of Chemical Industry

Pollinator shifts are considered to drive floral trait evolution, yet little is still known about the modifications of petal epidermal surface at a biogeographic region scale. Here we investigated how independent shifts from insects to passerine birds in the Macaronesian Islands consistently modified this floral trait (i.e. absence of papillate cells). Using current phylogenies and extensive evidence from field observations, we selected a total of 81 plant species and subspecies for petal microscopy and comparative analysis, including 19 of the 23 insular species pollinated by opportunistic passerine birds (Macaronesian bird-flowered element). Species relying on passerine birds as the most effective pollinators (bird-pollinated) independently evolved at least five times and in all instances associated with a loss of papillate cells, whereas species with a mixed pollination system (birds plus insects and/or other vertebrates) evolved at least five times in Macaronesia and papillate cells were lost in only 25% of these transitions. Our findings suggest that petal micromorphology is a labile trait during pollinator shifts and that papillate cells tend to be absent on those species where pollinators have limited mechanical interaction with flowers, including opportunistic passerine birds that forage by hovering or from the ground., A.V. was supported by RYC-2007-00620 and SEV-2012-0262 (Ministerio de Economía y Competitividad, Spain), A.O.-O. was funded by project CGL2011-2414 (Ministerio de Ciencia e Innovación, Spain), co-financed by European Regional Developmental Fund. J.F.-A. and A.G.F.d.C. were financed by project CGL2010-16138 (Ministerio de Ciencia e Innovación, Spain).

Background Intercalated disks are unique structures in cardiac tissue, in which adherens junctions, desmosomes, and GAP junctions co-localize, thereby facilitating cardiac muscle contraction and function. Protocadherins are involved in these junctions; however, their role in heart physiology is poorly understood. We aimed to analyze the transcriptomic profile of adhesion molecules in patients with ischemic cardiomyopathy (ICM) and relate the changes uncovered with the hemodynamic alterations and functional depression observed in these patients. Methods and Results Twenty-three left ventricular tissue samples from patients diagnosed with ICM (n = 13) undergoing heart transplantation and control donors (CNT, n = 10) were analyzed using RNA sequencing. Forty-two cell adhesion genes involved in cellular junctions were differentially expressed in ICM myocardium. Notably, the levels of protocadherin PCDHGA3 were related with the stroke volume (r = -0.826, P = 0.003), ejection fraction (r = -0.793, P = 0.004) and left ventricular end systolic and diastolic diameters (r = 0.867, P = 0.001; r = 0.781, P = 0.005, respectively). Conclusions Our results support the importance of intercalated disks molecular alterations, closely involved in the contractile function, highlighting its crucial significance and showing gene expression changes not previously described. Specifically, altered PCDHGA3 gene expression was strongly associated with reduced stroke volume and ventricular dysfunction in ICM, suggesting a relevant role in hemodynamic perturbations and cardiac performance for this unexplored protocadherin.

Background In dilated cardiomyopathy (DCM), cardiac failure is accompanied by profound alterations of extracellular matrix associated with the progression of cardiac dilation and left ventricular (LV) dysfunction. Recently, we reported alterations of non-fibrillar collagen expression in ischemic cardiomyopathy linked to fibrosis and cardiac remodeling. We suspect that expression changes in genes coding for non-fibrillar collagens may have a potential role in DCM development. Objectives This study sought to analyze changes in the expression profile of non-fibrillar collagen genes in patients with DCM and to examine relationships between cardiac remodeling parameters and the expression levels of these genes. Methods and Results Twenty-three human left ventricle tissue samples were obtained from DCM patients (n = 13) undergoing heart transplantation and control donors (n = 10) for RNA sequencing analysis. We found increased mRNA levels of six non-fibrillar collagen genes, such as COL4A5, COL9A1, COL21A1, and COL23A1 (P < 0.05 for all), not previously described in DCM. Protein levels of COL8A1 and COL16A1 (P < 0.05 for both), were correspondingly increased. We also identified TGF-beta 1 significantly upregulated and related to both COL8A1 and COL16A1. Interestingly, we found a significant relationship between LV mass index and the gene expression level of COL8A1 (r = 0.653, P < 0.05). Conclusions In our research, we identified new non-fibrillar collagens with altered expression in DCM, being COL8A1 overexpression directly related to LV mass index, suggesting that they may be involved in the progression of cardiac dilation and remodeling.

La narrativa transmedia parece ofrecer a las mujeres la liberación de estereotipos discriminatorios, arraigados en arquetipos ancestrales que las dominan. Sin embargo, los medios de comunicación dibujan una liberación que obvia la capacidad de respuesta de las mujeres. La tierra prometida de la libertad sexual, las hunde en el silencio de una masa que se ríe de los estereotipos del pasado y las desprotege sin voz para defenderlas de un presente que elimina las identidades de las mujeres. The transmedia narrative seems to offer women freedom from discriminating stereotypes which are rooted in ancient archetypes of power. However, mass media portrays a type of freedom which eliminates women’s right to reply. The promised land of sexual freedom, sinks women into a social silence which mocks stereotypes of the past while deprives them of voice to defend them from a present which erases the identities of the women. post-print 301 KB

The volume of health-care literature is growing at an increasing rate, with a huge amount of studies difficult to process. Therefore, we need tools or techniques to synthesize the information to help us in clinical decision-making. In fact, the available body of evidence ranges from single studies to umbrella reviews. In this scenario, evidence-based clinical decision-making requires knowing what type of evidence to use in every situation. However, a prerequisite for optimal decision-making is a greater understanding by professionals of the different techniques used to analyse their strengths, limitations and utilities. The purpose of this chapter is to take a journey from qualitative reviews to umbrella reviews. We start the tour on a fundamental point: term definitions, showing the variability among different authors. We go on to describe the differences, advantages, disadvantages and uses of different types of evidence, from individual studies to the ‘more specific methods’ for knowledge synthesis, both qualitative and quantitative syntheses (systematic reviews, meta-analysis, network meta-analysis). Finally, in the last part of our journey, we compare the strengths and weaknesses of different evidence synthesis methods from the more traditional or specific to the more general or broader reviews (umbrella reviews, overviews of reviews, meta-epidemiologic reviews). Systematic reviews are at the top of the evidence pyramid. However, the number of systematic reviews published is increasing at a high rate, and decision-makers need to evaluate more evidence to answer their questions. Systematic reviews of existing systematic reviews, known as umbrella reviews, provide an overall examination of the body of information that is available for a given topic. Despite the limitations and weaknesses of tools to appraise and synthesize evidence, systematic reviews and umbrella reviews, including overviews of reviews and meta-epidemiological studies, continue to be the best tool for an approximation to the truth, in evidence-based terms.

A collection of 143 plants arising from crosses from Monastrell × Cabernet Sauvignon is available in our orchards. A 3-year study enabled us to identify the differences between the different plants. In 2005, we had studied the anthocyanin profile and color characteristics of the most promising hybrids as a part of a project to select those plants showing the most interesting enological characteristics. Differences in the anthocyanin profile were observed between Monastrell and Cabernet Sauvignon grapes, the hybrids showing, in general, an anthocyanin profile intermediate between these two varieties, although closer to that of Cabernet Sauvignon grapes. To the best of our knowledge, this is the first work to study how the anthocyanin profile of two premium Vitis vinifera varieties is inherited by the resulting hybrid plants.

Cellular senescence is emerging as an important in vivo anticancer response elicited by multiple stresses, including currently used chemotherapeutic drugs. Nutlin-3a is a recently discovered small-molecule antagonist of the p53-destabilizing protein murine double minute-2 (MDM2) that induces cell cycle arrest and apoptosis in cancer cells with functional p53. Here, we report that nutlin-3a induces cellular senescence in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. No evidence of drug-induced apoptosis was observed in any case. Nutlin-induced senescence was strictly dependent on the presence of functional p53 as revealed by the fact that cells lacking p53 were completely insensitive to the drug, whereas cells lacking the tumor suppressor alternative reading frame product of the CDKN2A locus underwent irreversible cell cycle arrest. Interestingly, irreversibility was achieved in neoplastic cells faster than in their corresponding parental primary cells, suggesting that nutlin-3a and oncogenic signaling cooperate in activating p53. Our current results suggest that senescence could be a major cellular outcome of cancer therapy by antagonists of the p53-MDM2 interaction, such as nutlin-3a. [Cancer Res 2007;67(15):7350–7]

The morphology and composition of skin and pulp cell walls of four premium red wine grape (Vitis vinifera L.) varieties were studied to determine whether the technological differences observed in previous studies between the four different varieties during the winemaking process (especially, the anthocyanin extractability) could be partly explained by their respective cell wall compositions. Monastrell grapes showed the highest amount of cell wall material in their skins (55–57 mg cell wall/g skin), while Syrah showed the largest amount of cell wall material in the pulp (5.1 mg cell wall/g pulp). The highest percentage of galactose and cellulosic glucose in skin and pulp cell walls was also found in Monastrell grapes. The cell wall composition of Monastrell grapes, together with their morphology, suggests that the firmer pulp and skin are responsible for the difficulties this variety shows for anthocyanin extraction (extractability index varying from 37 to 60). As cell wall composition may be modulated by the action of enzymes, the activity of pectinmethylesterase, polygalacturonase, cellulase and α- and β-galactosidase was studied. No polygalacturonase and cellulase activity was found. The two galactosidases showed higher activity than pectinmethylesterase (25–290 units/g tissue versus 0.3–0.4 units/g tissue), especially in Cabernet Sauvignon grapes, although in Monastrell grapes α- and β-galactosidase activity was low, which may explain the large amount of galactose in Monastrell grapes cell wall.

In Anagyris foetida, a shrubby legume with autumn–winter flowering, the flowers produce great amounts of very dilute nectar during the first half of their life, consonant with their pollination by passeriforms. With advancing age, the volume of nectar diminishes and the concentration increases to values characteristic of bee‐pollinated flowers. The daily nectar secretion is greatest in volume early in the morning, damping during the day, whereas the concentration usually undergoes a gradual rise from morning to evening. The flowers visited for the first time in any day in the first half of anthesis have greater accumulated final nectar volumes than those first visited in the second half of anthesis. The accumulated nectar per flower is less in flowers that receive one visit per day than in those that receive three visits per day and is less in shrubby plants than in arboreal plants. In unvisited flowers, the rate of production of nectar depends on the environmental conditions, and at the end of their life...

In this work we describe a method for producing a tissue-detailed phantom of a mouse thorax, by means of durable and easy-to-get materials. We report the material selection and an implementation that involves mimicking tuberculosis lung granulomas and the surrounding tissues.

Approximately 30 % of the genera of Scrophulariaceae s.str. have a staminode, which is the remnant of a sterile stamen. However, there are no studies of the functionality or evolutionary pattern of staminodes in that family. This paper investigates three Scrophularia species with different staminode sizes to determine if the staminode safeguards nectar from dilution by rainwater and if it influences pollinator behavior. We also study staminode evolution and ancestral state reconstruction onto a phylogeny containing 71 species and subspecies with four different staminode developmental stages: tiny, large, enormous, and absent. The results showed that large staminodes did not hinder nectar collection or modify pollinator-visiting time but acted as a barrier to reduce rainwater entry. The latter reduced the dilution of nectar, which did not occur with tiny staminodes. The phylogenetic study revealed that the ancestral state in the genus corresponds with the presence of a large staminode vs. the tiny and enormous staminodes that are considered as derived. The complete disappearance of the staminode has occurred independently at least twice. Events occurred that increased or reduced the staminode size in one of the clades (Clade II), which includes species of sect. Caninae; most of these events occurred during the Pleistocene (0.6–2.7 Ma).

The composition of skin cell-walls from four different grape varieties (Vitis vinifera L., cv. Cabernet Sauvignon, Merlot, Syrah and Monastrell, the later harvested in three different locations) has been studied, trying to correlate those differences found in cell-wall composition among varieties with their degree of ripeness and with the easiness of anthocyanin extractability. The results of an anthocyanin extractability assay showed that the anthocyanins from Monastrell grape skins might be more difficult to extract than those from the other varieties. The study of the cell-wall composition showed some differences in uronic acids, cellulosic glucose, proteins and polyphenol content of cell-walls among varieties, and also differences between the Monastrell grapes cultivated in different locations were detected. Little differences could be found among the different samples regarding the non-cellulosic neutral sugars. In trying to look if differences in the extractability index were related to cell-wall composition and to help to clarify some of the mechanism involved in the anthocyanin extractability, a multiple regression analysis was conducted. The results showed that a model could be built up explaining a high percentage of the variability in the extractability index, using the content of the different components of the skin cell-wall as independent variables. Following this approach, the differences on the easiness of anthocyanin extractability in grape samples could be based in differences in pectin and cellulose content, but also, differences occurring on arabinoxylan, arabinogalactan and xyloglucan could be of importance.

The anthocyanin content and fingerprint of four different Vitis vinifera L. varieties (Cabernet Sauvignon, Merlot, Syrah and Monastrell), the last grown in two different locations, were studied during three growing seasons to determine how seasonal conditions and location affect the content of berry anthocyanins and their relative percentages. Important differences in the content of anthocyanins were detected among varieties—Monastrell grapes from one of the locations presenting the highest anthocyanin content—when expressed as µg g−1 of skin. However, due to the large berry size of Monastrell grapes, when the results were expressed as mg kg−1 of berry, Cabernet Sauvignon and Syrah grapes presented the highest concentration. Significant differences were found as regards growing season, the concentration of anthocyanins being lowest in 2003, the warmest year. As regards the relative percentage of the different anthocyanins, substantial differences were found between varieties, but again, the results were also influenced by the year under study. When the percentages of anthocyanins were used as variables in a discriminant analysis, a 100% correct classification of the four different varieties was obtained. Moreover, to check the suitability of this tool for classifying varieties, data referring to the anthocyanin percentages of the four varieties grown in very different agroecological conditions and at different ripening stages were tested with the model we have built, 89% of correct classification being achieved. Copyright © 2006 Society of Chemical Industry

The pollination of Anagyris foetida L. (Fabaceae), a Mediterranean species that is a relict of the Tertiary, was studied in two populations of SW Spain over a three-year period. Numerous censuses of birds and insects were carried out, the floral nectar was quantified, and specific tests were performed to determine the pollinators' pollen load, the pollen's effective transfer to the pistil, and spontaneous self-pollination. The most important pollinators were three species of passeriforms Phylloscopus collybita Vieillot, Sylvia atricapilla L. and S. melanocephala Gmelin - a result coherent with findings in populations of S and E Spain. The negligible existence of insect visitors and pollinators of A. foetida flowers could be explained by the early flowering of this species during the autumn-winter, coinciding with the coolest and wettest months of the year (cold, high winds, almost daily mists that persist until nightfall, and above all, abundant rainfall). The pollen loads carried by the birds were high, as were also the loads transferred to the pistil. The fruit-set of bagged flowers was very low, evidence of the plant's need for the birds as pollinators. This is the first proof of the existence of a native European bird-pollinated plant, since besides ifs peculaliarities (flowers odourless, pseudotubular, with no landing platform, pendulous, diurnal populations were mainly pollinated by three passeriform species.

5 x 0.5–1.7(2) mm, in whorls of 4, elliptic, ovate, orobovate, obtuse, attenuate or shortly petiolate, some-what fleshy, with the main vein more conspicuous,especially on the abaxial surface, and the lateral veinshardly visible, leaf margins occasionally slightly rev-olute, glabrous, finally reflexed, with ± abundant lin-ear oblique bundles of raphides, whitish, generally dryor absent in flowering. Partial inflorescences cymose,axillary, with 3 flowers, arranged in whorls, 4 in each,± approximate along the stems, on very short pedun-cles

Two new species of the genus Galium are described from the Iberian Peninsula: G. moralesianum OrtegaOlivencia & Devesa, and G. talaveranum Ortega-Olivencia & Devesa. The first grows on limestone or dolomiticlimestone outcrops in south-east Spain (the Segura and Gador mountain ranges) and shows morphological similarities with G. boissieranum Ehrend. & Krendl, which is endemic to southern Spain (mountains of Malaga). The second inhabits the margins of water courses, alder stands and cork-oak dehesas (parkland-type systems) of the west of the Iberian Peninsula, and is morphologically reminiscent of G. mollugo L. The chromosome numbers of these two species and of G. boissieranum are given. © 2003 The Linnean Society of London, Botanical Journal of the Linnean Society, 2003, 143, 177–187. ADDITIONAL KEYWORDS: Flora Iberica – karyology – taxonomy.

New combinations in Galium. Palabras clave. Galium, Península Ibérica, Rubiaceae, taxonomía.Key words. Ga/i/tm, Iberian Peninsula, Rubiaceae, taxonomy.

AimsPrevention of hospital readmissions is one of the main objectives in the management of patients with heart failure (HF). Most of the models predicting readmissions are based on data extracted from hospitalized patients rather than from outpatients. Our objective was to develop a validated score predicting 1-month and 1-year risk of readmission for worsening of HF in ambulatory patients. Methods and resultsA cohort of 2507 ambulatory patients with chronic HF was prospectively followed for a median of 3.3years. Clinical, echocardiographic, ECG, and biochemical variables were used in a competing risk regression analysis to construct a risk score for readmissions due to worsening of HF. Thereafter, the score was externally validated using a different cohort of 992 patients with chronic HF (MUSIC registry). Predictors of 1-month readmission were the presence of elevated natriuretic peptides, left ventricular (LV) HF signs, and estimated glomerular filtration rate (eGFR) 26mm/m(2), heart rate >70 b.p.m., LV HF signs, and eGFR 5% event rate) for 1-month HF readmission. Likewise, low-risk (7.8%), intermediate-risk (15.6%) and high-risk groups (26.1%) were identified for 1-year HF readmission risk. The C-statistics remained consistent after the external validation (

Objective Amelogenesis imperfecta (AI) is a group of clinically and genetically heterogeneous inherited conditions, causing alterations in the structure of enamel and chemical composition of enamel matrix during development. The objective of this study was to compare the clinical, radiographic, histological and immunohistochemical phenotypes of subjects affected with hypocalcified AI from three Chilean families and identify causal mutations in the FAM83H gene. Design The diagnosis was made using clinical, radiographic, histological and genealogical data from the patients, who were evaluated according to the classification criteria by Witkop. PCR and Sanger sequencing of the complete coding sequence and surrounding intron regions of the FAM83H gene were conducted. The structural study of the affected teeth was performed with light microscopy, scanning electron microscopy and immunohistochemistry. Results The probands of the three families were diagnosed with hypocalcified AI, but in only one of them the missense variant p.Gly557Cys was identified. This variant was not present in the SNP database or in 100 healthy controls and segregated with the disease in the affected family. Using light microscopy, a normal prismatic structure was observed in all three cases. However, the ultrastructure was found to be affected in two of the cases, showing persistence of organic matter including amelogenins. Conclusions These results suggest that FAM83H missense mutation reported in one of the families analyzed in this study might cause a phenotype of hypocalcified enamel more attenuated with retention of amelogenin.

Aims Disruptions in cardiac ion channels have shown to influence the impaired cardiac contraction in heart failure. We sought to determine the altered gene expression profile of this category in dilated cardiomyopathy (DCM) patients and relate the altered gene expression with the clinical signs present in our patients, such as ventricular dysfunction and sustained monomorphic ventricular tachycardia (SMVT). Methods and Results Left ventricular (LV) tissue samples were used in RNA-sequencing technique to elucidate the transcriptomic changes of 13 DCM patients compared to controls (n = 10). We analyzed the differential gene expression of cardiac ion channels, and we found a total of 34 altered genes. We found that the calcium channel CACNG8 mRNA and protein levels were down-regulated and highly and inversely related with LV ejection fraction (LVEF) (r = -0.78, P

Made available in DSpace on 2018-12-11T17:15:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-11-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Curcumin (CUR) has been used as photosensitizer in antimicrobial Photodynamic Therapy (aPDT). However its poor water solubility, instability, and scarce bioavalibility hinder its in vivo application. The aim of this study was to synthesize curcumin in polymeric nanoparticles (NP) and to evaluate their antimicrobial photodynamic effect and cytoxicity. CUR in anionic and cationic NP was synthesized using polylactic acid and dextran sulfate by the nanoprecipitation method. For cationic NP, cetyltrimethylammonium bromide was added. CUR-NP were characterized by physicochemical properties, photodegradation, encapsulation efficiency and release of curcumin from nanoparticles. CUR-NP was compared with free CUR in 10% dimethyl sulfoxide (DMSO) as a photosensitizer for aPDT against planktonic and biofilms (mono-, dual- and triple-species) cultures of Streptococcus mutans, Candida albicans and Methicillin-Resistant Staphylococcus aureus. The cytotoxicity effect of formulations was evaluated on keratinocytes. Data were analysed by parametric (ANOVA) and non-parametric (Kruskal-Wallis) tests (α = 0.05). CUR-NP showed alteration in the physicochemical properties along time, photodegradation similar to free curcumin, encapsulation efficiency up to 67%, and 96% of release after 48h. After aPDT planktonic cultures showed reductions from 0.78 log10 to complete eradication, while biofilms showed no antimicrobial effect or reductions up to 4.44 log10. Anionic CUR-NP showed reduced photoinactivation of biofilms. Cationic CUR-NP showed microbicidal effect even in absence of light. Anionic formulations showed no cytotoxic effect compared with free CUR and cationic CUR-NP and NP. The synthesized formulations improved the water solubility of CUR, showed higher antimicrobial photodynamic effect for planktonic cultures than for biofilms, and the encapsulation of CUR in anionic NP reduced the cytotoxicity of 10% DMSO used for free CUR. Department of Dental Materials and Prosthodontics School of Dentistry Araraquara São Paulo State University (UNESP) Department of Dental Materials and Prosthodontics School of Dentistry Araraquara São Paulo State University (UNESP) CAPES: 1732 FAPESP: 2013/07276-1 FAPESP: 2013/23165-5 FAPESP: 2014/18345-7 FAPESP: 2014/20119-5 CAPES: 30288 CAPES: 30641 CAPES: 34828 CAPES: 34848 CNPq: 446401/2014-5

UNLABELLED: Abstract Aims: A recent study conducted in mice reported that liver-specific knockout of tumor suppressor Pten augments nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcriptional activity. Here, we further investigated how phosphatase and tensin homolog deleted on chromosome 10 (PTEN) controls NRF2 and the relevance of this pathway in human carcin ogenesis.RESULTS: Drug and genetic targeting to PTEN and phosphoproteomics approaches indicated that PTEN leads to glycogen synthase kinase-3 (GSK-3)-mediated phosphorylation of NRF2 at residues Ser(335) and Ser(338) and subsequent beta-transducin repeat containing protein (β-TrCP)-dependent but Kelch-like ECH-associated protein 1 (KEAP1)-independent degradation. Rescue experiments in PTEN-deficient cells and xerographs in athymic mice indicated that loss of PTEN leads to increased NRF2 signature which provides a proliferating and tumorigenic advantage. Tissue microarrays from endometrioid carcinomas showed that 80% of PTEN-negative tumors expressed high levels of NRF2 or its target heme oxygenase-1 (HO-1).INNOVATION: These results uncover a new mechanism of oncogenic activation of NRF2 by loss of its negative regulation by PTEN/GSK-3/β-TrCP that may be relevant to a large number of tumors, including endometrioid carcinomas.CONCLUSION: Increased activity of NRF2 due to loss of PTEN is instrumental in human carcinogenesis and represents a novel therapeutic target. Antioxid. Redox Signal. 21, 2498-2514.