Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic

Reports from the Fifth EAHN Meeting in Tallinn

The fifth international meeting of the European Architectural History Network was held in Tallinn, at the National Library of Estonia, from 13 to 16 June 2018. The reports from this meeting aim to capture some of the main themes that came up during four intense days of academic discussions and exchange, meetings, and free-form interaction in different spatial and social settings. After the introduction by Andres Kurg, host of the Tallinn Meeting, five delegates review the five thematic tracks which organised the selected sessions and ran in parallel throughout the three days of the conference: Mediations, Comparative Modernities, Peripheries, Discovery and Persistence, and Body and Mind. In his closing keynote lecture, Reinhold Martin from Columbia University further reflected on the ample critical discussions which had taken place throughout the conference

Triggerpunkttherapie und Bewegungskontrolle bei Rückenschmerzen: Eine Fallserie

Zusammenfassung: Ziel der Arbeit: In der Fallserie wurde untersucht, ob manuelle Triggerpunkttherapie, ergänzt durch ein Bewegungskontrolltraining bei chronischen lumbalen Rückenschmerzen (CLRS) Alltagsfunktionen, Schmerzen und Bewegungskontrolle verbessern kann. Patienten und Methoden: Insgesamt 10Patienten wurden viermal einer manuellen Triggerpunkttherapie unterzogen, gefolgt von vier Trainingseinheiten zur Verbesserung der Bewegungskontrolle. Dabei wurden myofasziale Triggerpunkte (mTrP) im M.erector spinae zwischen Th10 und S3 und im M.quadratus lumborum behandelt. Der Roland-Morris Disability Questionnaire (RMDQ), die Patient-Specific Functional Scale (PSFS), die numerische Ratingskala (NRS) und 6Bewegungskontrolltests (MCT) dienten der Befunderhebung. Ergebnisse: Nach der Triggerpunkttherapie verbesserten sich die funktionellen Beeinträchtigungen deutlich (RMDQ von 7,7 auf 4,5; PSFS von 6,5 auf 3,8), die Schmerzen mäßig von 4,9 auf 3,1 (NRS) und die MCT leicht von 3,0 auf 2,4. Nach dem Training der Bewegungskontrolle sanken die Werte für den RMDQ und die PSFS nochmals leicht (3,3 und 3,2) und die MCT verbesserten sich deutlich (1,5). Ein 6-Monate-Follow-up zeigte weitere Verbesserungen beim RMDQ (2,3) und der NRS (3,0). Die PSFS blieb stabil (3,2). Schlussfolgerung: Die Kombination von Triggerpunkttherapie und Training der Bewegungskontrolle könnte geeignet sein, Funktionseinschränkungen von Patienten mit CLRS zu reduziere

Shadowing in the nuclear photoabsorption above the resonance region

A model based on the hadronic fluctuations of the real photon is developed to describe the total photonucleon and photonuclear cross sections in the energy region above the nucleon resonances. The hadronic spectral function of the photon is derived including the finite width of vector-meson resonances and the quark-antiquark continuum. The shadowing effect is evaluated considering the effective interaction of the hadronic component with the bound nucleons within a Glauber-Gribov multiple scattering theory. The low energy onset of the shadowing effect is interpreted as a possible signature of a modification of the hadronic spectral function in the nuclear medium. A decrease of the $\rho$-meson mass in nuclei is suggested for a better explanation of the experimental data.Comment: 8 pages, 7 figure

Towards a synthesized critique of neoliberal biodiversity conservation

During the last three decades, the arena of biodiversity conservation has largely aligned itself with the globally dominant political ideology of neoliberalism and associated governmentalities. Schemes such as payments for ecological services are promoted to reach the multiple ‘wins’ so desired: improved biodiversity conservation, economic development, (international) cooperation and poverty alleviation, amongst others. While critical scholarship with respect to understanding the linkages between neoliberalism, capitalism and the environment has a long tradition, a synthesized critique of neoliberal conservation - the ideology (and related practices) that the salvation of nature requires capitalist expansion - remains lacking. This paper aims to provide such a critique. We commence with the assertion that there has been a conflation between ‘economics’ and neoliberal ideology in conservation thinking and implementation. As a result, we argue, it becomes easier to distinguish the main problems that neoliberal win-win models pose for biodiversity conservation. These are framed around three points: the stimulation of contradictions; appropriation and misrepresentation and the disciplining of dissent. Inspired by Bruno Latour’s recent ‘compositionist manifesto’, the conclusion outlines some ideas for moving beyond critique

State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

Targeting SHP2 phosphatase in breast cancer overcomes RTK-mediated resistance to PI3K inhibitors

BACKGROUND: PI3K signaling is frequently activated in breast cancer and is targeted by PI3K inhibitors. However, resistance of tumor cells to PI3K inhibition, often mediated by activated receptor tyrosine kinases, is commonly observed and reduces the potency of PI3K inhibitors. Therefore, new treatment strategies to overcome resistance to PI3K inhibitors are urgently needed to boost their efficacy. The phosphatase SHP2, which plays a crucial role in mediating signal transduction between receptor tyrosine kinases and both the PI3K and MAPK pathways, is a potential target for combination treatment. METHODS: We tested combinations of PI3K and SHP2 inhibitors in several experimental breast cancer models that are resistant to PI3K inhibition. Using cell culturing, biochemical and genetic approaches, we evaluated tumor cell proliferation and signaling output in cells treated with PI3K and SHP2 inhibitors. RESULTS: Combination treatment with PI3K and SHP2 inhibitors counteracted both acquired and intrinsic breast cancer cell resistance to PI3K inhibition that is mediated by activated receptor tyrosine kinases. Dual PI3K and SHP2 inhibition blocked proliferation and led to sustained inactivation of PI3K and MAPK signaling, where resistant cells rapidly re-activated these pathways upon PI3K inhibitor monotreatment. In addition, we demonstrate that overexpression of SHP2 induced resistance to PI3K inhibition, and that SHP2 was frequently activated during the development of PI3K inhibitor resistance after prolonged treatment of sensitive cells. CONCLUSIONS: Our results highlight the importance of SHP2 as a player in resistance to PI3K inhibitors. Combination treatment with PI3K and SHP2 inhibitors could pave the way for significant improvements in therapies for breast cancer

Normalising jurisdictional heterotopias through place branding : the cases of Christiania and Metelkova

This paper explores the political dimensions of place branding as a path to normalisation for areas where a paradoxical relationship with the law exists, places that we coin “jurisdictional heterotopias” borrowing from Foucauldian literature. We posit that place branding plays a fundamental role in facilitating scale jumping in the otherwise vertically aligned legal space, a hierarchy designed to exclude spatial multiplicity from its premise. By examining the role of place branding in such areas, we endeavour to understand and appreciate the selective application of the law, the perpetuation of unregulated and illegal activity, as well as the place – specificity of legal practice. Ultimately, we argue that strong place branding associations permit the engulfment of this type of heterotopias in the “mainstream” leading to their normalisation; such a normalisation results not only in the acceptance of their uniqueness by the institutional elements, but also in the potential nullification of the liberties their communities advocate

Global Assemblages, Resilience, and Earth Stewardship in the Anthropocene

In this paper, we argue that the Anthropocene is an epoch characterized not only by the anthropogenic dominance of the Earth\u27s ecosystems but also by new forms of environmental governance and institutions. Echoing the literature in political ecology, we call these new forms of environmental governance “global assemblages”. Socioecological changes associated with global assemblages disproportionately impact poorer nations and communities along the development continuum, or the “Global South”, and others who depend on natural resources for subsistence. Although global assemblages are powerful mechanisms of socioecological change, we show how transnational networks of grassroots organizations are able to resist their negative social and environmental impacts, and thus foster socioecological resilience