Spatiotemporal analysis of breast cancer hospitalizations in Portugal in 2002–2016

Breast cancer (BC) is the most common cancer among Portuguese women and it is associated with high hospitalization rates. Therefore, this study aims to characterize the BC hospital admission rate (HAR) in women in the period of 2002-2016, with an additional focus on spatiotemporal patterns of hospitalizations by BC (main code). Methods: After a descriptive analysis of all BC hospitalizations, the main BC code HAR was studied using mapping techniques, analysis of spatiotemporal clusters, and analysis of spatial variations in temporal trends. Results: The BC-HAR was 118.72/105 women, showing a growth of 3.109% per year in this period. The median length of stay (LOS) in these patients was 5 days, and most cases were programmed surgical admissions. Several spatiotemporal clusters and spatial variations in temporal trends were detected. The seaside area of the country showed 4 high HAR clusters in the spatiotemporal analysis. Additionally, the seaside north of the country and 2 isolated counties presented significantly different temporal trends in BC-HAR versus the rest of the country. These clusters suggest regional asymmetries, as they showed differences in terms of: demographic characteristics (age at admission and rurality of county of residence), the type of admission, LOS, and outcomes of hospitalization. Conclusion: This study identified key areas of high BC-HAR and increasing trends for female HAR, providing evidence of spatial heterogeneities in this health indicator.publishersversionpublishe

Development and characterization of PLA nanoparticles as carriers for topical delivery

Nanoparticles are seen today as one of the best approaches for the delivery of drugs into the skin. Poly (Lactic Acid) (PLA) is biocompatible and biodegradable and already approved for clinical use. Thus, this work aimed to study the effect of several parameters on the properties of PLA nanoparticles (PLA-NPs) intended for topical delivery. The yield of nanoparticles formation and entrapment efficiencies of lipophilic and hydrophilic model compounds in PLA-NPs were assessed. We evaluated the effects of mechanical stirring, solvent composition and presence of tri-bloc polymers on the protocol for the production of PLA-NPs. The best protocol provided a monodispersed population of non-cytotoxic spherical particles of !150 nm and a yield of nanoparticles formation of !90%. This formulation also proved to be efficient in the encapsulation of lipophilic and hydrophilic model compounds (>80%). The best protocol for the production of PLA-NPs includes a nanoprecipitation step, which is easily up scalable

Interrupted aortic arch in a 58-year-old patient

A 58-year-old male patient was evaluated in the cardiology outpatient setting after an episode of hypertension and atrial fibrillation. He was also an ex-moker.Echocardiogram revealed slight left ventricular dilation with diastolic dysfunction and a systolic function in the lower normality level, as well as a rheumatic valvar disease with moderate mitral stenosis and slight aortic valve involvement, atrial enlargement and pulmonary hypertension. After an episode of acute pulmonar oedema the patient was referred for coronary catheterization. A right femoral approach was attempted and progression of the guidewire was not possible due to na interrupted aortic arch (IAA) (figure 1A), that was confirmed by right radial approach (figure 1B). The coronary arteries had no ignificant stenosis but the circumflex artery had an anomalous origin. A CT-scan confirmed an interrupted aortic arch (IAA) in the descending aorta, 27 mm below the left subclavian artery, and a short, 15-mm occluded segment Interrupted aortic arch in a 58-year-old patientcharacterized, originating from the right coronary Valsalva sinus and separated from the right coronary artery (figure 1D, arrow; figure 1F). The patient was submitted to cardiac correction surgery with the implantation of an intrapericardial Dacron conduit connecting both aortic ends. The periprocedural period was uneventful and at 1-year follow-up the patient was clinically stable with no cardiac complications. This IAA was an incidental finding, and it may have arisen from progression of an undiagnosed coarctation of the aorta while the absence of the ductus arteriosus was probably due to a progressive occlusion.info:eu-repo/semantics/publishedVersio

The enthalpies of dissociation of the N-O bonds in two quinoxaline derivatives

The present work reports the first experimental thermochemical study of mono-N-oxides derived from quinoxaline, namely, 3-methoxycarbonyl-2-methyl-quinoxaline N-oxide and 3-ethoxycarbonyl-2-methyl-quinoxaline N-oxide. The values of the enthalpies of formation, in the condensed state, and of the enthalpies of sublimation, derived from static bomb calorimetry and Calvet microcalorimetry measurements, respectively, are combined to derive the standard molar enthalpies of formation in the gaseous phase for these two compounds. From the latter values, the first and second N-O bond dissociation enthalpies for the corresponding di-N-oxides have been obtained. The gas-phase experimental results are also compared with calculated data obtained with a density functional theory approach. Copyright (c) 2008 John Wiley & Sons, Ltd

Kinetics of Expression in Cancer Drug Resistance

This research was funded by Fundação de Ciência e Tecnologia (FCT), grant number UID-BIM-00009-2020 and GHTM-UID/Multi/04413/2013. The APC was funded by Fundação de Ciência e Tecnologia (FCT), grant number UID-BIM-00009-2020.Cancer drug resistance (CDR) is a major problem in therapeutic failure. Over 90% of patients with metastatic cancer present CDR. Several mechanisms underlie CDR, including the increased expression of efflux ABC transporters and epigenetic phenomena. Nevertheless, a topic that is not usually addressed is the mechanism underlying the loss of CDR once the challenge to these cells is withdrawn. A KCR cell line (doxorubicin-resistant, expressing ABCB1) was used to induce loss of resistance by withdrawing doxorubicin in culture medium. ABCB1 activity was analysed by fluorescence microscopy and flow cytometry through substrate (DiOC2) retention assays. The expression of 1008 microRNAs was assessed before and after doxorubicin withdrawal. After 16 weeks of doxorubicin withdrawal, a decrease of ABCB1 activity and expression occurred. Moreover, we determined a signature of 23 microRNAs, 13 underexpressed and 10 overexpressed, as a tool to assess loss of resistance. Through pathway enrichment analysis, “Pathways in cancer”, “Proteoglycans in cancer” and “ECM-receptor interaction” were identified as relevant in the loss of CDR. Taken together, the data reinforce the assumption that ABCB1 plays a major role in the kinetics of CDR, and their levels of expression are in the dependence of the circuitry of cell miRNAspublishersversionpublishe

Synthesis, Characterization and Catalytic application of Water Stable η3-Allyl Dicarbonyl Complexes of Molybdenum(II)

Trabalho apresentado em EuropaCat X – Catalysis across disciplines, 28 Aug - 02 Sep 2011, Glasgow, ScotlandN/

The Complex Dynamic of Phase I Drug Metabolism in the Early Stages of Doxorubicin Resistance in Breast Cancer Cells

Funding: This research was partly funded by the Research Center grant ToxOmics (UIDB/00009/2020 and UIDP/0009/2020), from the Portuguese Fundação para a Ciência e a Tecnologia—FCTThe altered activity of drug metabolism enzymes (DMEs) is a hallmark of chemotherapy resistance. Cytochrome P450s (CYPs), mainly CYP3A4, and several oxidoreductases are responsible for Phase I metabolism of doxorubicin (DOX), an anthracycline widely used in breast cancer (BC) treatment. This study aimed to investigate the role of Phase I DMEs involved in the first stages of acquisition of DOX-resistance in BC cells. For this purpose, the expression of 92 DME genes and specific CYP-complex enzymes activities were assessed in either sensitive (MCF-7 parental cells; MCF-7/DOXS) or DOX-resistant (MCF-7/DOXR) cells. The DMEs genes detected to be significantly differentially expressed in MCF-7/DOXR cells (12 CYPs and eight oxidoreductases) were indicated previously to be involved in tumor progression and/or chemotherapy response. The analysis of CYP-mediated activities suggests a putative enhanced CYP3A4-dependent metabolism in MCF-7/DOXR cells. A discrepancy was observed between CYP-enzyme activities and their corresponding levels of mRNA transcripts. This is indicative that the phenotype of DMEs is not linearly correlated with transcription induction responses, confirming the multifactorial complexity of this mechanism. Our results pinpoint the potential role of specific CYPs and oxidoreductases involved in the metabolism of drugs, retinoic and arachidonic acids, in the mechanisms of chemo-resistance to DOX and carcinogenesis of BC.publishersversionpublishe

Improved Poly (D,L-lactide) nanoparticles-based formulation for hair follicle targeting

Objective Hair follicles are widely recognized as the preferential target and site of accumulation for nanoparticles after topical application. This feature is of particular importance for hair cosmetics, having the potential to refine the treatment of several hair follicle-related disorders. The aim of this work was to improve the preparation of Poly (D,L-lactide) (PLA) nanoparticles for in vivo follicular target and drug delivery. Methods Envisaging a future industrial scale-up of the process, nanoprecipitation method was used to prepare PLA nanoparticles: the effect of several processing parameters on their properties was examined and the yield of nanoparticles formation determined. Encapsulation efficiencies and in vitro release profiles of lipophilic and hydrophilic model compounds were also assessed. In vitro cytotoxicity and ex vivo penetration studies were performed on a reference skin cell line (NCTC2455, human skin keratinocytes) and porcine skin, respectively. Results Using acetone : ethanol (50 : 50, v/v) as the solvent phase, 0.6% (w/w) of Pluronic® F68 as a surfactant agent and agitation to mix the solvent and non-solvent phases, a monodispersed population of non-cytotoxic spherical nanoparticles of approximately 150 nm was obtained. The yield of nanoparticles for this formulation was roughly 90%. After encapsulation of model compounds, no significant changes were found in the properties of particles and the entrapment efficiencies were above 80%. The release kinetics of dyes from PLA nanoparticles indicate an anomalous transport mechanism (diffusion and polymer degradation) for Nile Red (lipophilic) and a Fickian diffusion of first order for fluorescein 5(6)-isothiocyanate (hydrophilic). Ex vivo skin penetration studies confirmed the presence of nanoparticles along the entire follicular ducts. Conclusions The optimized method allows the preparation of ideal PLA nanoparticles-based formulations for hair follicle targeting. PLA nanoparticles can effectively transport and release lipophilic and hydrophilic compounds into the hair follicles, and the yields obtained are acceptable for industrial purposes.Objectif Les follicules pileux sont largement reconnus comme la cible préférentielle et le site de l'accumulation des nanoparticules après application topique. Cette caractéristique est particulièrement importante pour les produits cosmétiques pour les cheveux, ayant la possibilité d'affiner le traitement de plusieurs troubles des follicules de cheveux. Le but de ce travail était d'améliorer la préparation de nanoparticules poly (D,L-lactide) (PLA) pour une administration folliculaire in vivo ciblée de drogues. Méthodes En envisageant un avenir à l’échelle industrielle du procédé, une méthode de nanoprécipitation a été utilisé pour préparer des nanoparticules de PLA: l'effet de plusieurs paramètres de traitement sur leurs propriétés a été examiné et le rendement de la formation des nanoparticules a été déterminé. Les efficacités d'encapsulation et de profils de libération in vitro de composés modèles lipophiles et hydrophiles ont également été évaluées. La cytotoxicité in vitro et ex vivo des études de pénétration a été effectuée sur une lignée de cellules de peau de référence (NCTC2455, des kératinocytes de peau humaine) et la peau de porc, respectivement. Resultats En utilisant l'acétone : éthanol (50 : 50, v/v) comme phase solvant, 0,6% (p/p) de Pluronic® F68 à titre d'agent tensioactif et l'agitation pour mélanger les phases de solvant et de non-solvant, une population monodispersée des nanoparticules sphériques non cytotoxiques d'environ 150 nm a été obtenue. Le rendement de nanoparticules pour cette formulation était d'environ 90%. Après encapsulation de composés modèles, aucune modification significative n'a été observée dans les propriétés des particules et les efficacités de piégeage ont été supérieures à 80%. La cinétique de libération de colorants de nanoparticules de PLA indique un mécanisme de transport anormal (diffusion et dégradation de polymère) pour le rouge Nil (lipophile) et une diffusion selon Fick de premier ordre pour FITC (hydrophile). Les études de pénétration ex vivo de la peau ont confirmé la présence de nanoparticules sur tous les conduits folliculaires. Conclusions La méthode optimisée permet la préparation de formulations à base de nanoparticules de PLA, idéales pour ciblage du follicule pileux. Les nanoparticules de PLA peuvent effectivement transporter et libérer des composés lipophiles et hydrophiles dans les follicules pileux; les rendements obtenus sont acceptables à des fins industrielles.The authors thank to the FCT Strategic Project PEst-OE/EQB/LA0023/2013 and to the Project “BioHealth – Biotechnology and Bioengineering approaches to improve health quality”, Ref. NORTE- 07-0124-FEDER-000027, co-funded by the Programa Operacional Regional do Norte (ON.2 – O Novo Norte), QREN, FEDER. This work was partly supported by FEDER through POFC–582 COMPETE and by Portuguese funds from FCT– Fundacão Para a Ciência e a Tecnologia through the project PEst-OE/BIA/UI4050/2014. The authors thank C. Botelho for technical assistance

The influence of dna repair genes variants

Funding: This research was funded by FCT—Fundação para a Ciência e a Tecnologia (Portuguese Foundation for Science and Technology) through Project UID/BIM/00009/2019—Centre for Toxicogenomics and Human Health.Radioiodine therapy with131I remains the mainstay of standard treatment for well-differentiated thyroid cancer (DTC). Prognosis is good but concern exists that131I-emitted ionizing radiation may induce double-strand breaks in extra-thyroidal tissues, increasing the risk of secondary malignancies. We, therefore, sought to evaluate the induction and 2-year persistence of micronuclei (MN) in lymphocytes from 26131I-treated DTC patients and the potential impact of nine homologous recombination (HR), non-homologous end-joining (NHEJ), and mismatch repair (MMR) polymorphisms on MN levels. MN frequency was determined by the cytokinesis-blocked micronucleus assay while genotyping was performed through pre-designed TaqMan® Assays or conventional PCR-restriction fragment length polymorphism (RFLP). MN levels increased significantly one month after therapy and remained persistently higher than baseline for 2 years. A marked reduction in lymphocyte proliferation capacity was also apparent 2 years after therapy. MLH1 rs1799977 was associated with MN frequency (absolute or net variation) one month after therapy, in two independent groups. Significant associations were also observed for MSH3 rs26279, MSH4 rs5745325, NBN rs1805794, and tumor histotype. Overall, our results suggest that131I therapy may pose a long-term challenge to cells other than thyrocytes and that the individual genetic profile may influence131I sensitivity, hence its risk-benefit ratio. Further studies are warranted to confirm the potential utility of these single nucleotide polymorphisms (SNPs) as radiogenomic biomarkers in the personalization of radioiodine therapy.publishersversionpublishe

High-yield synthesis and catalytic response of chainlike hybrid materials of the [(MoO3)m(2,2′-bipyridine)n] family

The one-dimensional organic–inorganic hybrid material [MoO3(2,2'-bipy)] (1) (2,2'-bipy = 2,2'-bipyridine) has been used as a starting material to prepare the bipy-deficient phases [Mo2O6(2,2'-bipy)] (2) and [Mo3O9(2,2'-bipy)2] (3) in excellent yields. The hybrid 2 was obtained by a solid-state thermal treatment of 1 (300 ºC, 10 min) while 3 was obtained by a hydrothermal treatment of 1 (160 ºC, 6 d). A study was performed to compare the catalytic properties of 1–3 in the epoxidation of cis-cyclooctene at 55 ºC with tert-butylhydroperoxide (TBHP) or aqueous H2O2 as oxidant. In all cases Cy was converted to cyclooctene oxide (CyO) with 100% selectivity, and Cy conversions increased in the order 1 < 3 < 2, which parallels an increase in the Mo/2,20-bipy molar ratio of the hybrid (1 < 1.5 < 2). With compound 2, CyO yields at 24 h were 96% for TBHP (cosolvent a,a,a-trifluorotoluene) and 53% for H2O2 (cosolvent CH3CN). The catalytic reactions occurred in homogeneous phase with active species formed in situ from 1–3. All three hybrids react with aqueous H2O2 to give the catalytically active oxodiperoxo complex [MoO(O2)2(2,2'-bipy)]. The 2 : 1 hybrid 2 was further examined for the epoxidation of other cyclic and linear non-functionalised olefins with TBHP, namely cyclododecene, 1-octene and trans-2-octene, and the biomass-derived olefins DL-limonene, a-pinene and methyl oleate.publishe