Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition

Given the high frequency of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe “on-target” gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application. Here, we demonstrate that genetic deletion or pharmacologic inhibition of the presenilin-1 (PSEN1) subclass of γ-secretase complexes is highly effective in decreasing leukemia while avoiding dose-limiting toxicities. Clinically, T-ALL samples were found to selectively express only PSEN1-containing γ-secretase complexes. The conditional knockout of Psen1 in developing T cells attenuated the development of a mutant NOTCH1-driven leukemia in mice in vivo but did not abrogate normal T cell development. Treatment of T-ALL cell lines with the selective PSEN1 inhibitor MRK-560 effectively decreased mutant NOTCH1 processing and led to cell cycle arrest. These observations were extended to T-ALL patient-derived xenografts in vivo, demonstrating that MRK-560 treatment decreases leukemia burden and increased overall survival without any associated gut toxicity. Therefore, PSEN1-selective compounds provide a potential therapeutic strategy for safe and effective targeting of T-ALL and possibly also for other diseases in which NOTCH signaling plays a role

Conservation performance of different conservation governance regimes in the Peruvian Amazon

State-controlled protected areas (PAs) have dominated conservation strategies globally, yet their performance relative to other governance regimes is rarely assessed comprehensively. Furthermore, performance indicators of forest PAs are typically restricted to deforestation, although the extent of forest degradation is greater. We address these shortfalls through an empirical impact evaluation of state PAs, Indigenous Territories (ITs), and civil society and private Conservation Concessions (CCs) on deforestation and degradation throughout the Peruvian Amazon. We integrated remote-sensing data with environmental and socio-economic datasets, and used propensity-score matching to assess: (i) how deforestation and degradation varied across governance regimes between 2006–2011; (ii) their proximate drivers; and (iii) whether state PAs, CCs and ITs avoided deforestation and degradation compared with logging and mining concessions, and the unprotected landscape. CCs, state PAs, and ITs all avoided deforestation and degradation compared to analogous areas in the unprotected landscape. CCs and ITs were on average more effective in this respect than state PAs, showing that local governance can be equally or more effective than centralized state regimes. However, there were no consistent differences between conservation governance regimes when matched to logging and mining concessions. Future impact assessments would therefore benefit from further disentangling governance regimes across unprotected land.This work was supported by the Economic and Social Research Council (grant number ES/I019650/1); Cambridge Political Economy Society; Cambridge Philosophical Society; St John’s College; and the Geography Department at the University of Cambridge

Fungal G-protein-coupled receptors::mediators of pathogenesis and targets for disease control

G-protein signalling pathways are involved in sensing the environment, enabling fungi to coordinate cell function, metabolism and development with their surroundings, thereby promoting their survival, propagation and virulence. G-protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in fungi. Despite the apparent importance of GPCR signalling to fungal biology and virulence, relatively few GPCR–G-protein interactions, and even fewer receptor-binding ligands, have been identified. Approximately 40% of current pharmaceuticals target human GPCRs, due to their cell surface location and central role in cell signalling. Fungal GPCRs do not belong to any of the mammalian receptor classes, making them druggable targets for antifungal development. This Review Article evaluates developments in our understanding of fungal GPCR-mediated signalling, while substantiating the rationale for considering these receptors as potential antifungal targets. The need for insights into the structure–function relationship of receptor–ligand interactions is highlighted, which could facilitate the development of receptor-interfering compounds that could be used in disease control

An α-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease [5] (multiple letters)

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