Geschichte der kriege und der bürgerbewaffnung Ulms, von den ältesten bis auf die jetzigen zeiten.

Mode of access: Internet.

Extracção de unigramas relevantes

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Engenharia Informática

Identifying and Targeting Molecular Deregulations in Uterine Leiomyosarcoma: A Role for mTOR Inhibition-Based Combination Therapies

Uterine leiomyosarcoma (ULMS) is an aggressive malignancy characterized by marked chemoresistance, frequent relapses, and poor outcome. Despite efforts to improve survival over the past several decades, only minimal advances have been made. Hence, there is an urgent and unmet need for better understanding of the molecular deregulations that underlay ULMS and development of more effective therapeutic strategies. This work identified several common deregulations in a large (n=208) tissue microarray of ULMS compared to GI smooth muscle, myometrium, and leiomyoma controls. Our results suggest that significant loss of smooth muscle and gynecological differentiation markers is common in ULMS, a finding that could help render improved ULMS diagnosis, especially for advanced disease. Similarly to reports in other malignancies, we found that several cancer-related proteins were differentially expressed; these could be useful together as biomarkers for ULMS. Notably, we identified significant upregulation and overexpression of the mTOR pathway in ULMS, examined the possible contribution of tyrosine kinase receptor deregulation promoting mTOR activation, and unraveled a role for pS6RP and p4EBP1 as molecular disease prognosticators. The significance of mTOR activation in ULMS and its potential as a therapeutic target were further investigated. Rapamycin abrogated ULMS cell growth and cell cycle progression in vitro but induced only sight growth delay in vivo. Given that effective mTOR therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora A kinase (Aurk A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated. Combined therapy with rapamycin (an mTORC1 inhibitor) and MLN8237 (an investigational Aurk A inhibitor) profoundly and synergistically abrogated ULMS growth in vitro. Interestingly, the superior effects were noted only when MLN8237 was pre-administered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo. Together, these data support further exploration of dual mTOR and Aurk A blockade for the treatment of human ULMS.

Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines.

BACKGROUND: To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma (uLMS) cell lines, and determine if dasatinib inhibits the SRC pathway. METHODS: SK-UT-1 and SK-UT-1B uLMS cells were treated with gemcitabine, docetaxel and dasatinib individually and in combination. SRC and paxcillin protein expression were determined pre- and post-dasatinib treatment using Meso Scale Discovery (MSD) multi-array immunogenicity assay. Dose-response curves were constructed and the coefficient of drug interaction (CDI) and combination index (CI) for drug interaction calculated. RESULTS: Activated phosphorylated levels of SRC and paxillin were decreased after treatment with dasatinib in both cell lines (p < 0.001). The addition of a minimally active concentration of dasatinib (IC25) decreased the IC50 of each cytotoxic agent by 2-4 fold. The combination of gemcitabine-docetaxel yielded a synergistic effect in SK-UT-1 (CI = 0.59) and an antagonistic effect in SK-UT-1B (CI = 1.36). Dasatinib combined with gemcitabine or docetaxel revealed a synergistic anti-tumor effect (CDI < 1) in both cell lines. The triple drug combination and sequencing revealed conflicting results with a synergistic effect in SK-UT-1B and antagonistic in SK-UT-1. CONCLUSION: Dasatinib inhibits the SRC pathway and yields a synergistic effect with the two-drug combination with either gemcitabine or docetaxel. The value of adding dasatinib to gemcitabine and docetaxel in a triple drug combination is uncertain, but may be beneficial in select uLMS cell lines. Based on our pre-clinical data and known activity of gemcitabine and docetaxel, further evaluation of dasatinib in combination with these agents for the treatment of uLMS is warranted.

A narrativa histórica de Alexandre Wollner sobre o design brasileiro em sua relação com arte, indústria e tecnologia

This work aims to investigate the historical narratives in which the graphic designer Alexandre Wollner assembled about the development of its own profession in Brazil, focusing the ways in which his discourse points relations among design (with greater emphasis in graphic design) and visual arts, the industrial development and notions about technology. Firstly, the theoretical setup searched for dialogues with design historians, with Mikhail Bakhtin, specially his concepts about “ideology” and “discourse’, and the theory of Field Autonomy by Pierre Bourdieu applied in the artistic practice. Following, the relation between Wollner’s own journey and the Brazilian industrial development is shown, and, at last, three of his historical texts are studied, which are written in different moments (1964; 1983; 1998), being those in which the analyzed author wished to point out the origens, events and names that are more remarkable. Throughout the work, it is pointed the importance of Wollner’s contact with the modernist european ideologies that share an abstract and rationalist matrix found at Hochschule für Gestaltung Ulm (HfG Ulm), the german design school from the city of Ulm, in the 1950s. Such modernist discourse understood the practice of design as a method with scientific character, being then different of some other more recurring artistic professional practices in some productive sectors. Wollner aimed to apply such ideals in his professional practice, being the foundation of the paulista office forminform, in 1958, one of his first expressions of such posture, and in his academic practice, helping the foundation of the Escola Superior de Desenho Industrial (ESDI), in Rio de Janeiro, in 1963. Such modernist ideals went along with moments of the Brazilian industrial development during the government of Juscelino Kubitschek (1956–1961) and the “Economical Miracle” from the military government (1968–1973). Wollner argued about the need for the development of national design as a technological and productive differential that would help the growth of national industry, based on Ulm’s project model concept. It is defended that Wollner’s professional and intelectual path, in his efforts of thinking a history of Brazilian design through the choice of pioneers in the area, was founded on an “ideal model” of design, leaving aside the modernist experiences from the 1950s. Such posture would indicate a search for validation of his own profession that was beginning to become more evident in Brazilian productive means, aiming the creation of a differential space in comparison with pre-established practices, usually link to graphic artists from the time.