Physicochemical Characterization of Hot Melt Extruded Bicalutamide–Polyvinylpyrrolidone Solid Dispersions

Solid molecular dispersions of bicalutamide (BL) and polyvinylpyrrolidone (PVP) were prepared by hot melt extrusion technology at drug-to-polymer ratios of 1:10, 2:10, and 3:10 (w/w). The solid-state properties of BL, physical mixtures of BL/PVP, and hot melt extrudates were characterized using differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), Raman, and Fourier transform infrared (FTIR) spectroscopy. Drug dissolution studies were subsequently conducted on hot melt extruded solid dispersions and physical mixtures. All hot melt extrudates had a single Tg between theTg of amorphous BL and PVP indicating miscibility of BL with PVP and the formation of solid molecular dispersions. PXRD con?rmed the presence of the amorphous form of BL within the extrudates. Conversely, PXRD patterns recorded for physical mixtures showed sharp bands characteristic of crystalline BL, whereas DSC traces had a distinct endotherm at 1968C corresponding to melting of crystalline BL. Further investigations using DSC con?rmed solid-state plasticization of PVP by amorphous BL and hence antiplasticization of amorphous BL by PVP. Experimentally observed Tg values of physical mixtures were shown to be signi?cantly higher than those calculated using the Gordon–Taylor equation suggesting the formation of strong intermolecular interactions between BL and PVP. FTIR and Raman spectroscopy were used to investigate these interactions and strongly suggested the presence of secondary interaction between PVP and BL within the hot melt extrudates. The drug dissolution properties of hot melt extrudates were enhanced signi?cantly in comparison to crystalline BL and physical mixtures. Moreover, the rate and extent of BL release were highly dependent on the amount of PVP present within the extrudate. Storage of the extrudates con?rmed the stability of amorphous BL for up to 12 months at 208C, 40% RH whereas stability was reduced under highly humid conditions (208C, 65% RH). Interestingly, BL recrystallization after storage under these conditions had no effect on the dissolution properties of the extrudates.

Understanding the Performance of Melt-Extruded Poly(ethylene oxide)–Bicalutamide Solid Dispersions: Characterisation of Microstructural Properties Using Thermal, Spectroscopic and Drug Release Methods

In this article, we have prepared hot-melt-extruded solid dispersions of bicalutamide (BL) using poly(ethylene oxide) (PEO) as a matrix platform. Prior to preparation, miscibility of PEO and BL was assessed using differential scanning calorimetry (DSC). The onset of BL melting was signi?cantly depressed in the presence of PEO, and using Flory– Huggins (FH) theory, we identi?ed a negative value of -3.4, con?rming miscibility. Additionally, using FH lattice theory, we estimated the Gibbs free energy of mixing which was shown to be negative, passing through a minimum at a polymer fraction of 0.55. Using these data, solid dispersions at drug-to-polymer ratios of 1:10, 2:10 and 3:10 were prepared via hot-melt extrusion. Using a combination of DSC, powder X-ray diffractometry and scanning electron
microscopy, amorphous dispersions of BL were con?rmed at the lower two drug loadings. At the 3:10 BL to PEO ratio, crystalline BL was detected. The percent crystallinity of PEO was reduced by approximately 10% in all formulations following extrusion. The increased amorphous content within PEO following extrusion accommodated amorphous BL at drug to polymer loadings up to 2:10; however, the increased amorphous domains with PEO following extrusion were not suf?cient to fully accommodate BL at drug-to-polymer ratios of 3:10.

Low pressure carbon dioxide solubility in pure electrolyte solvents for lithium-ion batteries as a function of temperature. Measurement and prediction

Experimental values for the carbon dioxide solubility in eight pure electrolyte solvents for lithium ion batteries – such as ethylene carbonate (EC), propylene carbonate (PC), dimethyl carbonate (DMC), ethyl methyl carbonate (EMC), diethyl carbonate (DEC), ?-butyrolactone (?BL), ethyl acetate (EA) and methyl propionate (MP) – are reported as a function of temperature from (283 to 353) K and atmospheric pressure. Based on experimental solubility data, the Henry’s law constant of the carbon dioxide in these solvents was then deduced and compared with reported values from the literature, as well as with those predicted by using COSMO-RS methodology within COSMOthermX software and those calculated by the Peng–Robinson equation of state implemented into Aspen plus. From this work, it appears that the CO2 solubility is higher in linear carbonates (such as DMC, EMC, DEC) than in cyclic ones (EC, PC, ?BL). Furthermore, the highest CO2 solubility was obtained in MP and EA solvents, which are comparable to the solubility values reported in classical ionicliquids. The precision and accuracy of the experimental values, considered as the per cent of the relative average absolute deviations of the Henry’s law constants from appropriate smoothing equations and from literature values, are close to (1% and 15%), respectively. From the variation of the Henry’s law constants with temperature, the partial molar thermodynamic functions of dissolution such as the standard Gibbs free energy, the enthalpy, and the entropy are calculated, as well as the mixing enthalpy of the solvent with CO2 in its hypothetical liquid state.

CD44 enhances invasion of basal-like breast cancer cells by upregulating serine protease and collagen-degrading enzymatic expression and activity

Introduction: Basal-like breast cancers (BL-BCa) have the worst prognosis of all subgroups of this disease. Hyaluronan (HA) and the HA receptor CD44 have a long-standing association with cell invasion and metastasis of breast cancer. The purpose of this study was to establish the relation of CD44 to BL-BCa and to characterize how HA/CD44 signaling promotes a protease-dependent invasion of breast cancer (BrCa) cells.

Methods: CD44 expression was determined with immunohistochemistry (IHC) analysis of a breast cancer tissue microarray (TMA). In vitro experiments were performed on a panel of invasive BL-BCa cell lines, by using quantitative polymerase chain reaction (PCR), immunoblotting, protease activity assays, and invasion assays to characterize the basis of HA-induced, CD44-mediated invasion.

Results: Expression of the hyaluronan (HA) receptor CD44 associated with the basal-like subgroup in a cohort of 141 breast tumor specimens (P = 0.018). Highly invasive cells of the representative BL-BCa cell line, MDA-MB-231 (MDA-MB-231Hi) exhibited increased invasion through a basement membrane matrix (Matrigel) and collagen. In further experiments, HA-induced promotion of CD44 signaling potentiated expression of urokinase plasminogen activator (uPA) and its receptor uPAR, and underpinned an increased cell-associated activity of this serine protease in MDA-MB-231Hi and a further BL-BCa cell line, Hs578T cells. Knockdown of CD44 attenuated both basal and HA-stimulated uPA and uPAR gene expression and uPA activity. Inhibition of uPA activity by using (a) a gene-targeted RNAi or (b) a small-molecule inhibitor of uPA attenuated HA-induced invasion of MDA-MB-231Hi cells through Matrigel. HA/CD44 signaling also was shown to increase invasion of MDA-MB-231 cells through collagen and to potentiate the collagen-degrading activity of MDA-MB-231Hi cells. CD44 signaling was subsequently shown to upregulate expression of two potent collagen-degrading enzymes, the cysteine protease cathepsin K and the matrix metalloprotease MT1-MMP. RNAi- or shRNA-mediated depletion of CD44 in MDA-MB-231Hi cells decreased basal and HA-induced cathepsin K and MT1-MMP expression, reduced the collagen-degrading activity of the cell, and attenuated cell invasion through collagen. Pharmacologic inhibition of cathepsin K or RNAi-mediated depletion of MT1-MMP also attenuated MDA-MB-231Hi cell invasion through collagen.

Conclusion: HA-induced CD44 signaling increases a diverse spectrum of protease activity to facilitate the invasion associated with BL-BCa cells, providing new insights into the molecular basis of CD44-promoted invasion.

Comparative study on performances of trimethyl-sulfonium and trimethyl-ammonium based ionic liquids in molecular solvents as electrolyte for electrochemical double layer capacitors

The present work reports a comparative study on the performances of two bis[(trifluoromethyl)sulfonyl]imide-based protic (PIL) and aprotic (AIL) ionic liquids, namely, trimethyl-ammonium bis[(trifluoromethyl)sulfonyl]imide ([HN][TFSI], PIL) and trimethyl-sulfonium bis[(trifluoromethyl) sulfonyl]imide ([S][TFSI], AIL), as mixtures with three molecular solvents: gamma butyrolactone (?-BL), propylene carbonate (PC), and acetonitrile (ACN) as electrolytes for supercapacitor applications. After an analysis of their transport properties as a function of temperature, cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and galvanostatic charge-discharge measurements were conducted at 25 and -30 C to investigate the performance of these mixtures as electrolytes for supercapacitors using activated carbon as the electrode material. Surprisingly, for each solvent investigated, no significant differences were observed between the electrolytes based on the PIL and AIL in their electrochemical performance due to the presence or the absence of the labile proton. Furthermore, good specific capacitances were observed in the case of ?-BL-based electrolytes even at low temperature. Capacitances up to 131 and 80 F·g are observed for the case of the [S][TFSI] + ?-BL mixture at 25 and -30 C, respectively. This latter result is very promising particularly for the formulation of new environmentally friendly electrolytes within energy storage systems even at low temperatures. © 2013 American Chemical Society.

Selection of burst-like transients and stochastic variables using multi-brand image differencing in the Pan-STARRS1 Medium Deep Survey

We present a novel method for the light-curve characterization of Pan-STARRS1 Medium Deep Survey (PS1 MDS) extragalactic sources into stochastic variables (SVs) and burst-like (BL) transients, using multi-band image-differencing time-series data. We select detections in difference images associated with galaxy hosts using a star/galaxy catalog extracted from the deep PS1 MDS stacked images, and adopt a maximum a posteriori formulation to model their difference-flux time-series in four Pan-STARRS1 photometric bands gP1, rP1, iP1, and zP1. We use three deterministic light-curve models to fit BL transients; a Gaussian, a Gamma distribution, and an analytic supernova (SN) model, and one stochastic light-curve model, the Ornstein-Uhlenbeck process, in order to fit variability that is characteristic of active galactic nuclei (AGNs). We assess the quality of fit of the models band-wise and source-wise, using their estimated leave-out-one cross-validation likelihoods and corrected Akaike information criteria. We then apply a K-means clustering algorithm on these statistics, to determine the source classification in each band. The final source classification is derived as a combination of the individual filter classifications, resulting in two measures of classification quality, from the averages across the photometric filters of (1) the classifications determined from the closest K-means cluster centers, and (2) the square distances from the clustering centers in the K-means clustering spaces. For a verification set of AGNs and SNe, we show that SV and BL occupy distinct regions in the plane constituted by these measures. We use our clustering method to characterize 4361 extragalactic image difference detected sources, in the first 2.5 yr of the PS1 MDS, into 1529 BL, and 2262 SV, with a purity of 95.00% for AGNs, and 90.97% for SN based on our verification sets. We combine our light-curve classifications with their nuclear or off-nuclear host galaxy offsets, to define a robust photometric sample of 1233 AGNs and 812 SNe. With these two samples, we characterize their variability and host galaxy properties, and identify simple photometric priors that would enable their real-time identification in future wide-field synoptic surveys.

SN 2010ay is a Luminous and Broad-lined Type Ic Supernova within a Low-metallicity Host Galaxy

We report on our serendipitous pre-discovery detection and follow-up observations of the broad-lined Type Ic supernova (SN Ic) 2010ay at z = 0.067 imaged by the Pan-STARRS1 3π survey just ~4 days after explosion. The supernova (SN) had a peak luminosity, MR ≈ -20.2 mag, significantly more luminous than known GRB-SNe and one of the most luminous SNe Ib/c ever discovered. The absorption velocity of SN 2010ay is v Si ≈ 19 × 103 km s-1 at ~40 days after explosion, 2-5 times higher than other broad-lined SNe and similar to the GRB-SN 2010bh at comparable epochs. Moreover, the velocity declines ~2 times slower than other SNe Ic-BL and GRB-SNe. Assuming that the optical emission is powered by radioactive decay, the peak magnitude implies the synthesis of an unusually large mass of 56Ni, M Ni = 0.9 M ⊙. Applying scaling relations to the light curve, we estimate a total ejecta mass, M ej ≈ 4.7 M ⊙, and total kinetic energy, EK ≈ 11 × 1051 erg. The ratio of M Ni to M ej is ~2 times as large for SN 2010ay as typical GRB-SNe and may suggest an additional energy reservoir. The metallicity (log (O/H)PP04 + 12 = 8.19) of the explosion site within the host galaxy places SN 2010ay in the low-metallicity regime populated by GRB-SNe, and ~0.5(0.2) dex lower than that typically measured for the host environments of normal (broad-lined) SNe Ic. We constrain any gamma-ray emission with E γ ~ 1048 erg. We therefore rule out the association of a relativistic outflow like those that accompanied SN 1998bw and traditional long-duration gamma-ray bursts (GRBs), but we place less-stringent constraints on a weak afterglow like that seen from XRF 060218. If this SN did not harbor a GRB, these observations challenge the importance of progenitor metallicity for the production of relativistic ejecta and suggest that other parameters also play a key role.

CD44-Mediated Activaton of α5β1-Intergrin, Cortactin and Paxillin Signaling Underpins Ashesion of basal-like breat cancer cells to Endotherlium and Fibronectin- enriched Matrices

CD44 expression is elevated in basal-like breast cancer (BLBC) tissue, and correlates with increased efficiency of distant metastasis in patients and experimental models. We sought to characterize mechanisms underpinning CD44-promoted adhesion of BLBC cells to vascular endothelial monolayers and extracellular matrix (ECM) substrates. Stimulation with hyaluronan (HA), the native ligand for CD44, increased expression and activation of β1-integrin receptors, and increased α5-integrin subunit expression. Adhesion assays confirmed that CD44-signalling potentiated BLBC cell adhesion to endothelium and Fibronectin in an α5B1-integrin-dependent mechanism. Co-immunoprecipitation experiments confirmed HA-promoted association of CD44 with talin and the β1-integrin chain in BLBC cells. Knockdown of talin inhibited CD44 complexing with β1-integrin and repressed HA-induced, CD44-mediated activation of β1-integrin receptors. Immunoblotting confirmed that HA induced rapid phosphorylation of cortactin and paxillin, through a CD44-dependent and β1-integrin-dependent mechanisms. Knockdown of CD44, cortactin or paxillin independently attenuated the adhesion of BL-BCa cells to endothelial monolayers and Fibronectin. Accordingly, we conclude that CD44 induced, integrin-mediated signaling not only underpins efficient adhesion of BLBC cells to BMECs to facilitate extravasation but initiates their adhesion to Fibronectin, enabling penetrant cancer cells to adhere more efficiently to underlying Fibronectin-enriched matrix present within the metastatic niche.

Prédiction de la digestibilité des acides aminés des ingrédients utilisés en alimentation porcine : approche par méta-analyse

En alimentation animale, l’utilisation adéquate des aliments nécessite une connaissance précise des valeurs nutritionnelles de leurs composantes, dont celle en acides aminés. Cependant, ces valeurs nutritionnelles dépendent de la teneur en acides aminés essentiels (AAE) totaux et de la digestibilité iléale standardisée (DIS) de ces AAE. Cette dernière varie en fonction de plusieurs facteurs, dont l’origine botanique des graines, les conditions de culture des récoltes, le stockage des aliments, les traitements physico-chimiques appliqués aux grains, les facteurs antinutritionnels (FANs) et les techniques expérimentales utilisées pour le dosage et l’estimation de la digestibilité des AAE. Une approche par méta-analyse a permis d’établir des modèles de prédiction de la valeur nutritionnelle en AAE des ingrédients à partir de leur composition chimique en considérant la protéine brute (PB), les AAE totaux, la teneur en fibre (Acid Detergent Fiber (ADF), Neutral Detergent Fiber (NDF) et Fibre Brute (FB)) et les FANs comme les inhibiteurs de la trypsine. En se référant à l’analyse graphique et statistique, les données ont été réparties en 4 groupes : 1) les tourteaux (tourteau de soja, colza/canola et coton); 2) les légumineuses (féveroles, lupins, pois et soja); 3) les céréales (blé, orge, avoine, sorgho et maïs); 4) les drêches de distilleries (blé et maïs). Ainsi, un modèle général ajusté en fonction du type d’ingrédients a été généré et les facteurs de variation de la digestibilité en AAE ont été identifiés. Pour les tourteaux, la DIS des AAE est réduite par un accroissement de la teneur en NDF, tandis que la DIS des AAE de la féverole, pois et lupin est principalement influencée par la teneur en PB et en FANs. Concernant les graines de soja la DIS des AAE est réduite par une hausse de la teneur en fibre (FB et ADF). Enfin pour les céréales et les sous- produit de céréales telles que les drêches, la PB et les fibres (ADF ou NDF) étaient les meilleurs nutriments pour prédire la DIS des AAE. Ces résultats démontrent que la DIS des AAE peut être prédite avec précision à partir de la composition chimique pour la plupart des ingrédients.

Animism in Rainforest and Tundra: Personhood, Animals, Plants and Things in Contemporary Amazonia and Siberia (Book Review)

Animism is a form of traditional spiritual belief that receives welcome treatment here. The observations of Victorian ethnologist travellers on the local peoples they regarded as primitive was analysed by Sir Edward (E. B.) Tylor, in Primitive Culture (1871) which established the working definition of animism followed by later generations of scholars. This came from the observation that non-scientific people did not always draw sharp distinctions between human persons and other entities such as animals, trees and even rocks but imbued these with soul. The latin anima, ‘soul, spirit’ provided the title of what was assumed to be a primitive religion, animism. The study being reviewed recognizes apparent connections within deep history between Siberia and the Amazon, and uses contemporary social anthropology to clarify assumptions about animism. This book on animism in two shamanic cultures explores personhood and the relations in pre-scientific human thought between humans and non-humans, in contexts where non-humans can be regarded as social persons (p.2).

Terpinen-4-ol: estudo do efeito sinérgico/aditivo, adesão em co-cultura e alteração dos fatores de virulência sobre Candida spp

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Reactivity of bulky tris(Phenylpyrazolyl) methanesulfonate copper(I) complexes towards small unsaturated molecules

Reaction of the tris(3-phenylpyrazolyl)methane sulfonate species (Tpms(Ph))Li with the copper(I) complex [Cu(MeCN)(4)][PF6] affords [Cu(Tpms(Ph))(MeCN)] 1. The latter, upon reaction with equimolar amounts of cyclohexyl-(CyNC) or 2,6-dimethylphenyl (XylNC) isocyanides, or excess CO, furnishes the corresponding Cu(I)complexes [Cu(Tpms(Ph))(CNR)] (R = Cy 2, Xyl 3) or [Cu(Tpms(Ph))(CO)] 4. The ligated isocyanide in 2 or 3 (or the acetonitrile ligand in 1)is displaced by 3-iminoisoindolin-1-one to afford 5, the first copper(I) complex containing an 3-iminoisoindolin-1-one ligand. The ligated acetonitrile in 1 undergoes nucleophilic attack by methylamine to give the amidine complex [Cu(Tpms(Ph)){MeC(NH)NHMe}] 6, whereas only the starting materials were recovered from the attempted corresponding reactions of 2 and 3 with methylamine. Complexes 1 or 6 form the trinuclear hydroxo-copper(II)species [(mu-Cu){Cu(mu-OH) (2)(Tpms(Ph))}(2)] 7 upon air oxidation in moist methanol. In all the complexes the scorpionate ligand facially caps the metal in the N,N,O-coordination mode.

Permeable Reactive Barriers using nanoparticles to remediate nitrate pollution

Nitrat e (NO3 - ) i s per vasi ve i n t he bi ospher e[ 1, 2]. Cont emporar y agri cult ural pr acti ces are a mong t he maj or ant hr opogeni c sources of r eacti ve nitrogen speci es, wher e nitrat ei s t he most abundant of t hese [ 2]. Excessi ve a mount s of r eacti ve nitrogen i n soil s and gr oundwat er ar e creati ng si gnifi cant t hr eat s t o hu man healt h and saf et y [ 3] as well as a host of undesirabl e environment al i mpact s [ 2]; it i s curr ently consi der ed t he second most r el evant environment al i ssue, aft er car bon di oxide e mi ssi ons. Nowadays, a mong t he most r el evant and pr omi si ng appr oaches t o r educe nitrat e concentrati on i n wat er, na mel y gr oundwat er, ar e denitrifi cati on- based pr ocesses [ 4]. Per meabl e r eacti ve barri ers ( PRB) have been pr oven eff ecti ve i n r educi ng vari ous cont ami nant s i n copi ous a mount s, parti cul arl y i n shall ow gr oundwat er [ 5]. However t he possi bl e added eff ecti veness of usi ng nanoparti cl es i n t hese structur es t o obt ai n nitrogen gas from nitrat es requires f urt her i nvesti gati on.

Lounais-Suomen pohjavesien toimenpideohjelma vuoteen 2015

Kaikissa EU-maissa on laadittu ensimmäiset vesienhoitosuunnitelmat, joiden avulla tavoitellaan pinta- ja pohjavesien hyvää tilaa vuonna 2015. Pohjavesin osalta tavoitteena on pohjavesien hyvä kemiallinen ja määrällinen tila. Vesienhoito on osa koko Euroopan laajuista, vesipolitiikan puitedirektiiviin pohjautuvaa työtä. Kokemäenjoen-Saaristomeren-Selkämeren vesienhoitoalueelle laaditussa vesienhoitosuunnitelmassa asetettujen tavoitteiden saavuttamiseksi on Lounais-Suomen alueen pohjavesille laadittu toimenpideohjelma. Lisäksi alueelle on laadittu kaksi pintavesien hoidon toimenpideohjelmaa, joista toinen Varsinais-Suomeen ja toinen Satakuntaan. Lounais-Suomen pohjavesien toimenpideohjelmaan vuoteen 2015 on koottu tiedot pohjavettä heikentävistä toiminnoista, riskipohjavesialueista ja selvityskohteista sekä pohjavesien määrällisestä ja kemiallisesta tilasta. Toimenpideohjelmassa esitetään myös tärkeimmät toimenpiteet, joiden avulla pohjavesien määrällinen ja kemiallinen hyvä tila pyritään saavuttamaan ja ylläpitämään vuoteen 2015 mennessä. Pohjavesien osalta tarkastelu kohdistuu vedenhankinnan kannalta tärkeisiin pohjavesialueisiin (luokka I) ja vedenhankintaan soveltuviin pohjavesialueisiin (luokka II). Lounais-Suomessa pohjavesialueita on yhteensä 295, joista I-luokan alueita on 219 kappaletta ja II-luokan alueita 76 kappaletta. Toimenpideohjelmassa tarkastellaan tarkemmin pohjavesialueita, joilla pohjaveden tila on heikentynyt tai hyvä tila on uhattuna ihmistoiminnasta johtuen. Lounais-Suomen alueella merkittävimmät pohjavettä vaarantavat ja muuttavat toiminnot ovat teollisuus ja yritystoiminta, pilaantuneet maa-alueet, liikenne ja tienpito sekä asutus ja maankäyttö. Myös maa-ainesten otolla, maa- ja metsätaloudella sekä vedenotolla ja tekopohjaveden muodostamisella voi olla pohjaveden laatua heikentäviä vaikutuksia. Riskialueiksi nimettiin 34 pohjavesialuetta, selvityskohteiksi 48 ja seurantakohteiksi 5 pohjavesialuetta. Huonoon tilaan on kemiallisen tilan arvioinnin kautta luokiteltu 9 pohjavesialuetta, joiden ongelmat johtuvat mm. torjunta-aineista, kloridista, liuottimista, polttonesteiden lisäaineista ja raskasmetalleista. Pohjavesien määrällinen tila on kaikilla Lounais-Suomen pohjavesialueilla hyvä. Kemiallisen hyvän tilan saavuttaminen ja sen ylläpitäminen vaativat toimenpiteitä, joista tärkeimpiä ovat riskitoimintojen ohjaaminen pohjavesialueiden ulkopuolelle, pohjavesien suojelusuunnitelmat, pilaantuneiden maa-alueiden tutkimukset ja kunnostukset sekä tiealueiden pohjavesisuojausten rakentaminen. Pohjavesien hyvää kemiallista tilaa ei saavuteta kaikilla pohjavesialueilla vuoteen 2015 mennessä, vaikka esitetyt toimenpiteet toteutettaisiin. Toimenpideohjelma tarkistetaan kuuden vuoden välein, jolloin arvioidaan uudestaan pohjavesien tila ja toimet pohjavesien hyvän tilan saavuttamiseksi.