A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer.

Serous Ovarian Cancers (SOC) are frequently resistant to programmed cell death. However, here we describe that these programmed death-resistant cells are nonetheless sensitive to agents that modulate autophagy. Cytotoxicity is not dependent upon apoptosis, necroptosis, or autophagy resolution. A screen of NCBI yielded more than one dozen FDA-approved agents displaying perturbed autophagy in ovarian cancer. The effects were maximized via combinatorial use of the agents that impinged upon distinct points of autophagy regulation. Autophagosome formation correlated with efficacy in vitro and the most cytotoxic two agents gave similar effects to a pentadrug combination that impinged upon five distinct modulators of autophagy. However, in a complex in vivo SOC system, the pentadrug combination outperformed the best two, leaving trace or no disease and with no evidence of systemic toxicity. Targeting the autophagy pathway in a multi-modal fashion might therefore offer a clinical option for treating recalcitrant SOC

PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases

Targeting the αvβ3/NGR2 Pathway in Neuroendocrine Prostate Cancer

Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in vitro functional assays, we here demonstrate that NgR2 is crucial in promoting cell adhesion to αVβ3 ligands. Moreover, we describe for the first time co-fractionation of αVβ3 integrin and NgR2 in small extracellular vesicles derived from metastatic prostate cancer patients\u27 plasma. These prostate cancer patient-derived small extracellular vesicles have a functional impact on human monocytes, increasing their adhesion to fibronectin. The monocytes incubated with small extracellular vesicles do not show an associated change in conventional polarization marker expression and appear to be in an early stage that may be defined as adhesion competent . Overall, these findings allow us to better understand integrin-directed signaling and cell-cell communication during cancer progression. Furthermore, our results pave the way for new diagnostic and therapeutic perspectives for patients affected by neuroendocrine prostate cancer

Descolonizar la economía: espacios de economías diversas y ontologías mapuche en Alto Biobío, Chile

Mapuche economies have been commonly described as closed and focused only on subsistence, making the ways in which they contribute to and diversify the economy invisible. Examining the case of Trekaleyin, a Mapuche-Pewenche tourism initiative in Alto Biobio, this paper explores the economic context in which it was developed from a diverse and de-colonial perspectives. Based on fieldwork using ethnographic and Participatory Action-Research methodologies, this article brings together debates within geography on diverse economies and post-development and elements of Mapuche ontologies. The results presented, then, are based on the recognition and detailed analysis of multiple practices, actors and ontologies at play within these economic arrangements, which reach beyond capitalism. The paper concludes by considering these diverse elements, which are usually excluded from the economy, are key in recognizing the performative, hybrid and negotiated nature of economic arrangements, and in moving towards a decolonization of ideas and practices on the economy and development.Las economías mapuche han sido comúnmente descritas como cerradas y de subsistencia, invisibilizando cómo contribuyen y diversifican la economía. Examinando el caso de Trekaleyin, una iniciativa turística mapuche-pewenche en Alto Biobío, este artículo explora desde perspectivas diversas y decoloniales las configuraciones económicas en las que está articulada. Basado en trabajo de campo usando metodologías etnográficas y de investigación-acción, este artículo entrelaza debates actuales dentro de la geografía en torno a las economías diversas y el postdesarrollo con aspectos de las ontologías mapuche. Los resultados presentados corresponden al reconocimiento y análisis detallado de las múltiples prácticas, actores y ontologías en juego en estos ensamblajes económicos que van más allá del capitalismo. Se concluye que considerar estos elementos diversos usualmente excluidos de lo económico es crucial para reconocer el carácter performativo, híbrido y negociado de los ensamblajes económicos, y para avanzar hacia ideas y prácticas descolonizadoras acerca de la economía y el desarrollo

Indigeneity, Autonomy and New Cultural Spaces: The Decolonisation of Practices, Being and Place through Tourism in Alto Bío-Bío, Chile

This thesis explores the engagement of a group of Mapuche-Pewenche communities with tourism in southern Chile. I argue that Trekaleyin, their tourism initiative, is part of a broader and long history of resistance and struggles for autonomy, territory and decolonisation, in which identity, development, agency and relations with other beings are negotiated, revitalised and re-produced. From my experience working as a development practitioner with these communities in the beginnings of Trekaleyin, I became interested in understanding the ways in which, as a collective experience, it is embedded in and articulated with political concerns and contestation with regards to neoliberalism and multiculturalism. I also became interested in how the communities are incorporating and reactivating diverse and solidarity economies in their work on tourism, while at the same time reworking their relations with and the market economy itself. I suggest that through Trekaleyin, the communities are also re-producing a relational and open sense of place and connectivity, mobilising particular ways of knowing, being and relating to territory and more-than-human beings in a context of global neoliberalism, reshaping scales and their possibilities. With this thesis I aim to explore how, through their engagement in tourism, community members are disrupting, expanding and hybridising discourses and practices around development, the economy, nature and cross-cultural relations, reworking them so as to craft a better position from where they can participate in them, but the consequences of which extend beyond the “local”, affecting us all, both indigenous and non-indigenous. Therefore, from an ethnographic site and poststructural, post-human and decolonising geographic approaches, this thesis brings new perspectives to the study of development, tourism and the environment, particularly among indigenous peoples, in which autonomy, hybridity, diversity and relational ontologies are articulated

The Well of Trencin

Story set in 14th century Slovakia Illustrations by Max Kellere

Die Arbeiterinnenfrage : Vortrag

Aus: Arbeiterpräses ; 1910,4/5

III. Estudio del comportamiento de uranio, molibdeno y otros elementos en columnas de resina de intercambio aniónico

1. Se estudian las constantes de elución de diversos elementos en resina de intercambio aniónico en ciclo sulfato, encontrándose que solamente se fijan en estas condiciones el UVI, MoVI, VV y parcialmente el FeIII.2. Se establece un procedimiento de separación de UVI Y FeIII y otro de UVI Y MoVI.3. Con resultados obtenidos se señala un método para la separación y determinación de uranio en minerales que lo contengan