A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2

Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo, despite elevated expression levels of COX-2 in Nf2-deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms

The medical student

The Medical Student was published from 1888-1921 by the students of Boston University School of Medicine

Practicing food anxiety: Making Australian mothers responsible for their families’ dietary decisions

Concerns about the relationship between diet, weight, and health find widespread expression in the media and are accompanied by significant individual anxiety and responsibilization. However, these pertain especially to mothers, who undertake the bulk of domestic labor involved in managing their families’ health and wellbeing. This article employs the concept of anxiety as social practice to explore the process whereby mothers are made accountable for their families’ dietary decisions. Drawing on data from an Australian study that explored the impact of discourses of childhood obesity prevention on mothers, the article argues that mothers’ engagements with this value-laden discourse are complex and ambiguous, involving varying degrees of self-ascribed responsibility and blame for children's weight and diets. We conclude by drawing attention to the value of viewing food anxiety as social practice, in highlighting issues that are largely invisible in both official discourses and scholarly accounts of childhood obesity prevention

Governing food and agriculture in a warming world

In order to understand, how, why and whether the trade-offs and tensions around simultaneous implementation of the SDGs are resolved in ways which are both sustainable and equitable requires an appreciation of power relations across multiple scales of governance. We explore the politics and political economy of how the nexus around food-energy and water is being governed through initiatives to promote ‘climate-smart agriculture’ (CSA) as it moves from the global to the local. We combine analysis of how these interrelationships are being governed (and ungoverned) by key global institutions with reflection upon the consequences of this for developing countries that are being targeted by CSA initiatives. In particular, we look at Kenya as a country heavily dependent on agriculture, but also subject to some of the worst effects of climate change, and which has been targeted by a range of bilateral and multilateral donors with their preferred vision of CSA. We draw on strands of literature in global environmental politics (GEPs), political ecology and the political economy of development to make sense of the power dynamics which characterize the multi-scalar politics of how CSA is translated, domesticated and operationalized in practice

Collage Vol. II

JUDY COCHRAN: Editorial, 4-5 ROBERTA CHAPMEN: Photo, 6 ANITRA CHUGHTAI (Translations): Haikus, 7 CHARLES O\u27KEEFE: Photo, 8 MARK VANDERLINDE-ABERNATHY, ALYSSA LANDRY (Translator): Memories of a Spider (Les souvenirs d\u27une araignee), 9 MARK VANDERLINE-ABERNATHY, AMY NORSKOG (Translator): Tomato Fields (Champ de tomates), 10 SARAH BISHOP, HEFEDH ZANINA (Translator): Dear John (Cher John), 11 RYAN BUTZ (Translator): Basho\u27s Haiku, Issa\u27s Haiku, 12-13 JENNIFER HUMBERT, FADOUA EL BOUAMRAOUI (Translator): Pressed Lips (Levres Serrees), 15 ADELE REEVES (Translator): Contemporary song by Mr. Children, 16-17 BRODY PAGEL, GRACE DUGAR (Translator): The Lizard King (Le Roi Lezard), 18 JIMMY PIPKIN (Translator): In Love with You, 19 MOLLY ROSCOE: Saturday Night at Rusty\u27s (Samedi Soir a Rusty\u27s), 20 CHARLES O\u27KEEFE: Photo, 21 MATT MESSMER (Translator): Waseda University School Song, 22-23 TIMOTHY COOPER: Wenn du grosh bist… (When you\u27re Tall…), 24 DAVID HARMAN: Der Dunkle Stern (The Dark Star), 25 ANN TOWNSEND, JUDY COCHRAN (Translator): From a Window (D\u27une Fenetre), 26-27 SARA CAHILL: El sauce lloron (The Weeping Willow), 28-32 CHARLES O\u27KEEFE: Photo, 30 JENNIFER HUMBERT, MATT BISHOP: Past, Present (passe, present), 33 CAROL GENEYA KAPLAN, FADOUA EL BOUAMRAOUI (Translator): Une Autre Femme (Another Woman), 34-35 CHARLES O\u27KEEFE: Photo, 36 ANN TOWNSEND, JUDY COCHRAN (Translator): The Mowers (Les Faucheurs), 37 PRISCILLA PATON: Photo, 38 GONZALO TUESTA: La Grande Dame De Paris (The Great Lady of Paris), 39 SARAH PILLERDORF (Translator): Japanese Cartoons by Tezuka Osamu, 41-45 DANIELLE GERKEN: Schuhe der Heimat (Boots of Home), 47 CURTIS PLOWGIAN: Le peste de la langue francaise, 48-52 PRISCILLA PATON: Photo, 50 ZANE HOUSEHOLDER: Vive la Republique! (Film), 54 JENNIFER ZIMMER: EL tenis y las frustraciones (Tennis and Frustrations), La tumba de Ben (Ben\u27s Grave), 56-57 AUTUMN LOTZE: Times Square in the rain, 58-59 CHARLES O\u27KEEFE: Photo, 60 STEPHEN M. JULKA: Colors of the Earth, 61 THOMAS BRESSOUD: Java, 62 ERIC NELSON: World, 63 SARAH CLAPP (Translator): At a long day\u27s end (Natsume Soseki), A friend has come and is now leaving, Eating persimmons (Masaoka Shiki), 64 CHARLES O\u27KEEFE: Photo, 65 JOHN BURZYNSKI, MEGAN FETTER (Translator): Home is where the heart is, 66 RICHARD BANAHAN: Photo, 67 KIM FREEMAN: Baltimore, 68 JACOB RIDRIGUEZ-NOBLE: Home (Heimat), 69 SUZANNE KENNEDY: Oft verberge ich mich (Oft I hide myself), 70 RICHARD BANAHAN: Photo, 7

THE CONCISE GUIDE TO PHARMACOLOGY 2019/20 : G protein- coupled receptors

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.Peer reviewe