69 research outputs found

    Investigation of particle accumulation, chemosensitivity and thermosensitivity for effective solid tumor therapy using thermosensitive liposomes and hyperthermia

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    Doxorubicin (Dox) loaded thermosensitive liposomes (TSLs) have shown promising results for hyperthermia-induced local drug delivery to solid tumors. Typically, the tumor is heated to hyperthermic temperatures (41-42 °C), which induced intravascular drug release from TSLs within the tumor tissue leading to high local drug concentrations (1-step delivery protocol). Next to providing a trigger for drug release, hyperthermia (HT) has been shown to be cytotoxic to tumor tissue, to enhance chemosensitivity and to increase particle extravasation from the vasculature into the tumor interstitial space. The latter can be exploited for a 2-step delivery protocol, where HT is applied prior to i.v. TSL injection to enhance tumor uptake, and after 4 hours waiting time for a second time to induce drug release. In this study, we compare the 1- and 2-step delivery protocols and investigate which factors are of importance for a therapeutic response. In murine B16 melanoma and BFS-1 sarcoma cell lines, HT induced an enhanced Dox uptake in 2D and 3D models, resulting in enhanced chemosensitivity. In vivo, therapeutic efficacy studies were performed for both tumor models, showing a therapeutic response for only the 1-step delivery protocol. SPECT/CT imaging allowed quantification of the liposomal accumulation in both tumor models at physiological temperatures and after a HT treatment. A simple two compartment model was used to derive respective rates for liposomal uptake, washout and retention, showing that the B16 model has a twofold higher liposomal uptake compared to the BFS-1 tumor. HT increases uptake and retention of liposomes in both tumors models by the same factor of 1.66 maintaining the absolute differences between the two models. Histology showed that HT induced apoptosis, blood vessel integrity and interstitial structures are important factors for TSL accumulation in the investigated tumor types. However, modeling data indicated that the intraliposomal Dox fraction did not reach therapeutic relevant concentrations in the tumor tissue in a 2-step delivery protocol due to the leaking of the drug from its liposomal carrier providing an explanation for the observed lack of efficacy

    Alinhamento interpessoal, representacional e morfossintático na Gramática Discursivo-Funcional

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    Este artigo se debruça sobre o mapeamento entre os Níveis Interpessoal, Representacional e Morfossintático da gramática, o chamado alinhamento, segundo o arcabouço da Gramática Discursivo-Funcional (GDF). Propõe uma tipologia das línguas baseada no que a sua organização morfossintática codifica: distinções pragmáticas (p.ex. em Tagalo), distinções semânticas (p.ex. em Achém), ou distinções inerentes à morfossintaxe (p.ex. em Inglês, Basco ou a língua Kham). A inclusão tanto do Sujeito como do Objeto e de línguas tanto acusativas como ergativas no tratamento do alinhamento morfossintático permitiu-nos abranger tipos tipologicamente mais variáveis e demonstrar o potencial da GDF para a análise contrastiva das línguas.<br>Within the framework of Functional Discourse Grammar (FDG), alignment concerns the relations between the Interpersonal, Representational and Morphosyntactic Levels of grammar. This article proposes a typology of languages based upon what we find to be encoded in their morphosyntactic organization: pragmatic distinctions (as in Tagalog), semantic distinctions (as in Acheh), or distinctions inherent to the morphosyntax (as in English, Basque and Kham). By including both subject and object, and both accusative and ergative languages in our treatment of morphosyntactic alignment, we provide a better coverage of typological variation and show the potential of FDG for cross-linguistic analysis

    Homer, Hymn To Apollo 402-3

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