Biodegradable drug-eluting stents: Targeting urothelial tumors of upper urinary tract

INTRODUCTION & OBJECTIVES: Urothelial tumors of upper urinary tract are ranked among the most common types of cancers worldwide. The current standard therapy to prevent recurrence is intravesical Bacillus Calmetteâ Guerin (BCG) immunotherapy, but it presents several disadvantages such as BCG failure and intolerance. Another way is to use chemotherapy, which is generally better tolerated that BCG. In this case, drugs such as epirubicin, doxorubicin, paclitaxel and gemcitabine are used. Nevertheless, intravesical chemotherapy only prevents recurrence in the short-term. These failings can be partially attributed to the short residence time and low bioavailability of the drug within the upper urinary tract and the cancer cells, resulting in a need for frequent drug instillation. To avoid these problems, biodegradable ureteral stents impregnated by supercritical fluid CO2 (SCF) with each of the four anti-cancer drugs were produced. MATERIAL & METHODS: Four formulations with different concentrations of gelatin and alginate and crosslink agent were tested and bismuth was added to confer radiopaque properties to the stent. The preliminary in vivo validation studies in female domestic pigs was conducted at the University of Minho, Braga, after formal approval by the institutionâ s review board and in accordance with its internal ethical protocol for animal experiments. Paclitaxel, epirubicin, doxorubicin and gemcitabine were impregnated in the stents and the release kinetics was measured in artificial urine solution (AUS) for 9 days by UV spectroscopy in a microplate reader. The anti-tumoral effect of the developed stents in transitional cell carcinoma (TCC) and HUVEC primary cells, used as control, was evaluated. RESULTS: The in vivo validation of this second-generation of ureteral stents performed was herein demonstrated. Biodegradable ureteral stents were placed in the ureters of a female pigs, following the normal surgical procedure. The animals remained asymptomatic, with normal urine flow. The in vitro release study in AUS of the stent impregnated showed a higher release in the first 72h for the four anti-cancer drugs impregnated after this time the plateau was achieved and the stent degraded after 9 days. The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. CONCLUSIONS: The use of biodegradable ureteral stent in urology clinical practice not only reduce the stent-related symptoms but also open new treatment therapyâ s, like in urothelial tumors of upper urinary tract. Furthermore, we have demonstrated the clinical validation in vivo pig model. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells.The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells

Targeting urothelial tumors of upper urinary tract with drug-eluting stents impregnated by supercritical fluids

Urothelial tumors of upper urinary tract are ranked among the most common types of cancers worldwide and it has been considered as one of the more expensive to treat due of its long-term propensity of recurrence. The current standard therapy to prevent recurrence is intravesical Bacillus Calmette–Guerin (BCG) immunotherapy, but it presents several disadvantages such as BCG failure and intolerance. Another way is to use chemotherapy, that has been reported to be generally better tolerated that BCG. In this case, drugs such as epirubicin, doxorubicin, paclitaxel and gemcitabine are used. Nevertheless, intravesical chemotherapy only prevents recurrence in the short-term[1], [2]. These failings can be partially attributed to the short residence time and low penetration of the drug within the upper urinary tract and the cancer cells, resulting in a need for frequent drug instillation [3]. To avoid these problems, biodegradable ureteral stents impregnated by supercritical fluid CO2 (SCF) with each of the four anti-cancer drugs were produced (figure 1). Four types of drug-eluting biodegradable stents were studied, impregnated with paclitaxel, epirubicin, doxorubicin and gemcitabine. The release kinetics of the impregnated drugs from the anti-cancer drug-eluting stents was measured in artificial urine solution (AUS) for 9 days. The in vitro drugs release from the impregnated biodegradable ureteral stents was analyzed using a microplate reader. The in vitro release study in AUS showed a higher release in the first 72h for the four anti-cancer drugs impregnated after this time the plateau was achieved and the stent degrades after 9 days. Regarding the amount of impregnated drugs by SCF the gemcitabine showed higher amount (109 μg) and the lower amount was obtained for paclitaxel (67 ng). The diffusion coefficient and the impregnation yield were calculated. The anti-tumoral effect of the developed stents in transitional cell carcinoma (TCC) - T24 cell lines was evaluated. T24 cell line was exposed to graded concentrations (0.01 to 2000 ng/ml) of the four drugs for both 4 and 72 hours to determine the sensitivities to each drug (IC50). Toxicity as a result of both direct and indirect contact of the cell lines with the different material conditions of biodegradable stent were studied. The four anti-cancer drugs showed a concentrationdependent inhibitory effect on the T24 and HUVEC cell lines with IC50’s for paclitaxel of 7.30ng and 501.50ng, respectively. The T24 cell line shows to be more sensitive than HUVEC cell line for all the anti-cancer drugs tested. The direct and indirect contact of the anti-cancer biodegradable stents with the T24 and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the T24 cell line after 72h and no killing effect in the HUVEC cells. Finally, this study has shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the T24 cell lines, with no toxicity observed in the control, non-cancerous cells.Luso­- American Foundation's Grant for Internships in the University of California, Berkeley, 2015/CON5/CAN8; FCT PhD Grant (SFRH/BD/97203/2013); European Union's Seventh Framework Programme (FP7/2007­2013) under grant agreement n° REGPOT­CT2012­316331­ POLARIS; Project “Novel smart and biomimetic materials for innovative regenerative medicine approaches (Ref.: RL1 ­ ABMR ­ NORTE­01­0124­FEDER­000016)” cofinanced by North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF

Micropartículas de óleo de pequi obtidas por coacervação complexa com goma de cajueiro e gelatina.

Uma das técnicas de encapsulamento mais recomendadas para bioativos de natureza lipofílica é a coacervação complexa. Consiste na interação de polímeros catiônicos e aniônicos solúveis em água, que formam uma fase rica em polímeros, denominados de coacervados complexos. O emprego desta técnica é vantajoso por ser simples e a precipitação dos coacervados ocorrer facilmente em condições de temperaturas baixas (cerca de 10 ºC). Neste trabalho, está descrito como proceder para a formação de micropartículas de óleo de pequi (óleo de pequi microencapsulado) a partir de matrizes de goma de cajueiro e gelatina bovina utilizando-se a técnica de coacervação complexa. Estas matrizes foram escolhidas em razão do caráter aniônico e catiônico da goma de cajueiro (um polissacarídeo ainda sem valor econômico agregado) e gelatina (uma proteína de baixo custo), respectivamente.bitstream/item/199764/1/COT19007.pd

TECHNOLOGICAL CHARACTERISTICS OF THE WOOD OF Eucalyptus grandis W.Hill ex Maiden AND Eucalyptus cloeziana F. Muell, AS A SUPPLY FOR THE FURNITURE INDUSTRY

Este trabalho se desenvolveu na Universidade de Bras\uedlia e no Laborat\uf3rio de Produtos Florestais (IBAMA), Bras\uedlia, DF. Foram estudadas duas esp\ue9cies de eucalipto ( Eucalyptus grandis W.Hill ex Maiden e Eucalyptus cloeziana ) para confec\ue7\ue3o de pe\ue7as mobili\ue1rias. A madeira de E. grandis apresenta propriedades f\uedsicas (densidade e retratibilidade) e mec\ue2nicas (flex\ue3o est\ue1tica e dureza) extremamente positivas para a ind\ufastria moveleira, sendo complementado por seu bom desempenho perante equipamentos e m\ue1quinas, al\ue9m de receber bem produtos de acabamento. A cor da madeira e o seu desenho levaram os consumidores a mostrar \uf3tima aceita\ue7\ue3o do m\uf3vel fabricado com a esp\ue9cie. A madeira de Eucalyptus cloeziana, apesar de mostrar propriedades f\uedsicas e mec\ue2nicas com valores mais elevados que as do Eucalyptus grandis W.Hill ex Maiden, apresenta caracter\uedsticas desejadas para ind\ufastria moveleira. A sua colora\ue7\ue3o cinza oliva \ue9 uma op\ue7\ue3o para o consumidor. Alguns cuidados especiais com essa esp\ue9cie dever\ue3o ser tomados durante opera\ue7\uf5es com m\ue1quinas e equipamentos. Os valores da propriedade dureza apresentados por essa madeira a indicam para fabrica\ue7\ue3o de piso.This work was carried out at Universidade de Bras\uedlia at the Wood Products of Forestry Laboratory (IBAMA, Bras\uedlia, DF, Brazil). Two species of eucalypt wood ( Eucalyptus grandis W.Hill ex Maidenand Eucalyptus cloeziana ) were studied to supply the furniture making industry. The wood of Eucalyptus grandis W.Hill ex Maiden shows physical properties (density and retractibility) and mechanical properties (static bending and hardness) very suitable for the industry of wood furniture. Such characteristics are complemented by its excellent behaviour in machining and also good finishing with varnishes. The colour and patterns the wood bring to the consumers a good feeling as well as for the furnitures built with such a species. The wood of Eucalyptus cloeziana, in spite of its mechanical and physical properties higher than those of Eucalyptus grandis W.Hill ex Maiden, presents good characteristics for the manufacture of furniture. Its grey-olive colouring is consistent with a good choice and taste for the consumers. However, some precaution must be observed during the machining of the wood. This wood\u2019s hardness makes it suitable for parquetry

Determinants of the exclusive breastfeeding abandonment: psychosocial factors

OBJECTIVE To assess the determinants of exclusive breastfeeding abandonment. METHODS Longitudinal study based on a birth cohort in Viçosa, MG, Southeastern Brazil. In 2011/2012, 168 new mothers accessing the public health network were followed. Three interviews, at 30, 60, and 120 days postpartum, with the new mothers were conducted. Exclusive breastfeeding abandonment was analyzed in the first, second, and fourth months after childbirth. The Edinburgh Postnatal Depression Scale was applied to identify depressive symptoms in the first and second meetings, with a score of ≥ 12 considered as the cutoff point. Socioeconomic, demographic, and obstetric variables were investigated, along with emotional conditions and the new mothers’ social network during pregnancy and the postpartum period. RESULTS The prevalence of exclusive breastfeeding abandonment at 30, 60, and 120 days postpartum was 53.6% (n = 90), 47.6% (n = 80), and 69.6% (n = 117), respectively, and its incidence in the fourth month compared with the first was 48.7%. Depressive symptoms and traumatic delivery were associated with exclusive breastfeeding abandonment in the second month after childbirth. In the fourth month, the following variables were significant: lower maternal education levels, lack of homeownership, returning to work, not receiving guidance on breastfeeding in the postpartum period, mother’s negative reaction to the news of pregnancy, and not receiving assistance from their partners for infant care. CONCLUSIONS Psychosocial and sociodemographic factors were strong predictors of early exclusive breastfeeding abandonment. Therefore, it is necessary to identify and provide early treatment to nursing mothers with depressive symptoms, decreasing the associated morbidity and promoting greater duration of exclusive breastfeeding. Support from health professionals, as well as that received at home and at work, can assist in this process

The Drosophila GIPC Homologue Can Modulate Myosin Based Processes and Planar Cell Polarity but Is Not Essential for Development

Epithelia often show, in addition to the ubiquitous apico-basal (A/B) axis, a polarization within the plane of the epithelium, perpendicular to the A/B axis. Such planar cell polarity (PCP) is for example evident in the regular arrangement of the stereocilia in the cochlea of the mammalian inner ear or in (almost) all Drosophila adult external structures. GIPCs (GAIP interacting protein, C terminus) were first identified in mammals and bind to the Gαi GTPase activating protein RGS-GAIP. They have been proposed to act in a G-protein coupled complex controlling vesicular trafficking. Although GIPCs have been found to bind to numerous proteins including Frizzled receptors, which participate in PCP establishment, there is little in vivo evidence for the functional role(s) of GIPCs. We show here that overexpressed Drosophila dGIPC alters PCP generation in the wing. We were however unable to find any binding between dGIPC and the Drosophila receptors Fz1 and Fz2. The effect of overexpressed dGIPC is likely due to an effect on the actin cytoskeleton via myosins, since it is almost entirely suppressed by removing a genomic copy of the Myosin VI/jaguar gene. Surprisingly, although dGIPC can interfere with PCP generation and myosin based processes, the complete loss-of-function of dGIPC gives viable adults with no PCP or other detectable defects arguing for a non-essential role of dGIPC in viability and normal Drosophila development