Inhibition of focal adhesion kinase suppresses the adverse phenotype of endocrine-resistant breast cancer cells and improves endocrine response in endocrine-sensitive cells

International audienceAcquired resistance to endocrine therapy in breast cancer is a major clinical problem. Previous reports have demonstrated that cell models of acquired endocrine resistance have altered cell–matrix adhesion and a highly migratory phenotype, features which may impact on tumour spread in vivo. Focal adhesion kinase (FAK) is an intracellular kinase that regulates signalling pathways central to cell adhesion, migration and survival and its expression is frequently deregulated in breast cancer. In this study, we have used the novel FAK inhibitor PF573228 to address the role of FAK in the development of endocrine resistance. Whilst total-FAK expression was similar between endocrine-sensitive and endocrine-resistant MCF7 cells, FAK phosphorylation status (Y397 or Y861) was altered in resistance. PF573228 promoted a dose-dependent inhibition of FAK phosphorylation at Y397 but did not affect other FAK activation sites (pY407, pY576 and pY861). Endocrine-resistant cells were more sensitive to these inhibitory effects versus MCF7 (mean IC for FAK pY397 inhibition: 0.43 μM, 0.05 μM and 0.13 μM for MCF7, TamR and FasR cells, respectively). Inhibition of FAK pY397 was associated with a reduction in TamR and FasR adhesion to, and migration over, matrix components. PF573228 as a single agent (0–1 μM) did not affect the growth of MCF7 cells or their endocrine-resistant counterparts. However, treatment of endocrine-sensitive cells with PF573228 and tamoxifen combined resulted in greater suppression of proliferation versus single agent treatment. Together these data suggest the importance of FAK in the process of endocrine resistance, particularly in the development of an aggressive, migratory cell phenotype and demonstrate the potential to improve endocrine response through combination treatment

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Auswirkungen von G72 Expression auf kognitive Funktionen<em> in vivo </em>sowie auf mitochondriale Funktionen <em>in vitro</em>

In der hier vorgestellten Dissertation wurde die Funktion des Gens G72 untersucht. Neben in vivo Versuchen zu kognitiven Defiziten G72/G30-transgener Mäuse wurde die biologische Funktion des Proteins G72-1 und einer weiteren Splicevariante von G72 (G72-4) in vitro analysiert. Zur Untersuchung kognitiver Fähigkeiten G72-transgener Tiere wurde die Fähigkeit des tonabhängigen Furchterlernens untersucht. G72/G30 Tiere zeigten im Gegensatz zu Wildtyp Tieren Defizite im Erlernen der konditionierten Furchtreaktion. Dieses Ergebnis steht im Einklang mit bereits publizierten Ergebnissen bezüglich kognitiver Fähigkeiten G72-transgener Tiere sowie mit erwiesenen Assoziationen von G72 mit kognitiven Fähigkeiten im Menschen. Bis dato wird die Funktion von G72-1 kontrovers diskutiert. Die in dieser Arbeit hergestellten transgenen Zellen konnten wichtige Ergebnisse zur subzellulären Lokalisation und der mitochondrialen Funktion liefern. G72-4 wurde in dieser Arbeit zum ersten Mal überhaupt untersucht. Die mitochondriale Lokalisation von G72-1 in Zellen aus unterschiedlichsten Spezies sowie unterschiedlichster geweblicher Herkunft untestützt die Hypothese der mitochondrialen Funktion dieses bisher kontrovers diskutierten Proteins. Vermutlich spielt G72-1 eine wichtige Rolle in der Regulation des oxidativen Stress in den Zellen. Es konnten in dieser Arbeit Veränderungen im Glutathion-System sowie eine gesteigerte Aktivität der mitochondrialen Aconitase beobachtet werden. G72-4 hingegen war in den transgenen Cos7 Zellen sowohl cytosolisch als auch mitochondrial lokalisiert. G72-4 modulierte in Cos7 Zellen die Aktivität des Komplex I. Die verstärkte Komplex I Aktivität führte in unserem Zellsystem vermutlich zu vermehrter Wasserstoffperoxidproduktion. Weder G72-1 noch G72-4 modulierten die Aktivität der Citrat Synthase, das Maß für die Funktionsfähigkeit der Mitochondrien und die Geschwindigkeit des Citratzyklus. Die Ergebnisse deuten insgesamt auf eine Feinregulierung der mitochondrialen Funktion, vor allem des Metabolismus reaktiver Sauerstoffspezies, durch G72 hin

EFFECTS OF DIRECT INSTRUCTION ON THE ACQUISITION OF PREPOSITIONS BY STUDENTS WITH INTELLECTUAL DISABILITIES

Some students with intellectual disabilities require explicit instruction of language skills, including preposition use; however, little is known about effective ways to teach preposition use to this population. This study examined direct instruction (DI) to teach students to use and respond to prepositions. Results indicated that DI was an effective way to teach prepositions. Limitations and directions for future research are discussed

Migratory destinations and spatial structuring of humpback whales (Megaptera novaeangliae) wintering off Nicaragua

Abstract Understanding the migratory patterns of large whales is of conservation importance, especially in identifying threats to specific populations. Migration ecology, including migratory destinations, movements and site fidelity for humpback whales (Megaptera novaeangliae) remain poorly studied in parts of the range of the Central America population, considered endangered under the United States Endangered Species Act. This study aimed to investigate the migratory destinations of humpback whales sighted at two study sites in Nicaragua, which are part of the Central America population. A ten-year photographic database of humpback whales observed off Nicaragua was combined with citizen science contributions and sightings from dedicated research programs. The resulting image collection was compared with available historical photo identifications and databases using an automated image recognition algorithm. This approach yielded 36 years of photographic identification totaling 431 recaptures in Nicaragua (2006–2008 and 2016–2021) and 2539 recaptures (1986–2020) in both feeding and breeding grounds of 176 unique individuals sighted in Nicaragua. Our results showed that photo-identified whales were recaptured between October and April in breeding grounds and year-round in feeding grounds between British Columbia and California, with peak recaptures between June and October. Our study provided first-time evidence on fine-scale site affinity of individual humpback whales within Nicaraguan waters and to other breeding and feeding grounds