Nature Medicine Contents: June 2012 Volume 18 Number 6 pp 835-987

TABLE OF CONTENTS June 2012 Volume 18, Issue 6 Podcast Editorial News Book Review News and Views Between Bedside and Bench Research Highlights Review Articles Letters Technical Reports Japanese table of contents Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement 2013 Vilcek Prizes for Creative Promise The Vilcek Foundation is seeking young, foreign-born biomedical scientists to apply for the $35,000 Creative Promise Prizes. Three winners will be selected. Applicants must be 38 years old or younger, have a doctoral degree, and hold a position as principal investigators in an academic or research institution. More at www.vilcek.org.   Advertisement Nature Outlook: Malaria The past attempts to eradicate malaria have failed. What will it take to finally subdue this deadly disease? Access the Outlook free online for six months. Produced with support from: Medicines for Malaria Venture (MMV), Sigma-Tau, Vestergaard Frandsen New York   Advertisement Nature Outlook: Diabetes 5% of the world's population are afflicted by either type 1 diabetes, an autoimmune disorder, or type 2 diabetes, largely linked to lifestyle. Nature Outlook: Diabetes examines the latest research into the causes, therapy, prevention and impact of these devastating diseases. Access the Outlook free online for six months. Produced with support from: Eli Lilly and Company   Nature Medicine Podcast  Top Talk of the brown  We discuss how to turn white fat into brown fat and a new species-spanning approach to biomedicine. Listen Now Editorial Top Beyond cost considerations   p835 doi:10.1038/nm.2842 Novartis's recent legal action against the UK National Health Service to prevent the off-label use of Avastin for macular degeneration challenges the current regulatory structures ensuring accountability for the safety and quality of drugs. News Top Clinical trial website struggles to serve as research data hub   p837 Monica Heger doi:10.1038/nm0612-837 Pharma backs latest attempt at a global health R&D treaty   p838 Rebecca Hersher doi:10.1038/nm0612-838a Corrections   p838 doi:10.1038/nm0612-838b Paper reveals new channels for worry over long QT syndrome   p839 Roxanne Palmer doi:10.1038/nm0612-839a Panel proposes framework for FDA to evaluate drug risks   p839 Trevor Stokes doi:10.1038/nm0612-839b Drugs targeting mGluR5 receptor offer 'fragile' hope for autism   p840 Sarah C P Williams doi:10.1038/nm0612-840 Recommendation of HIV test brings diagnostic dilemma home   p841 Cassandra Willyard doi:10.1038/nm0612-841 Sequencing cells one at a time offers singular insight into cancer   pp842 - 843 Jeanne Erdmann doi:10.1038/nm0612-842a Cancer drug's survivin suppression called into question   pp842 - 843 David Holmes doi:10.1038/nm0612-842b A history of drugs on the weight list   p843 Elie Dolgin doi:10.1038/nm0612-843 News in Brief Biomedical briefing   pp844 - 845 doi:10.1038/nm0612-844 Q&A Straight talk with...Joseph Schwartz   p846 Mark Ratner doi:10.1038/nm0612-846 Since last November, six biopharma buyouts have exceeded $1 billion each, with Gilead Sciences' purchase last year of the hepatitis C specialist Pharmasset topping the charts at a whopping $11.2 billion, the highest ever paid for a clinical-stage biotech and an 89% premium to its share price at the time. Mark Ratner sought out biopharma analyst Joseph Schwartz, a managing director at Leerink Swann in Boston, for his views on what’s behind the recent buyout spending. News Feature The vetting process   pp847 - 849 Katharine Gammon doi:10.1038/nm0612-847 Humans and other animals suffer from many of the same ailments. Yet, aside from cases in which diseases cross the species barrier, veterinarians and physicians rarely work together to tackle common health problems. That may soon change. Katharine Gammon profiles one cardiologist who is pioneering a species-spanning approach to biomedical research. Opinion Take Russia to 'task' on bioweapons transparency   p850 Raymond A. Zilinskas doi:10.1038/nm0612-850 In the run-up to his reelection, Russian president Vladimir Putin outlined 28 tasks to be undertaken by his administration, including one that commanded the development of weapons based on [ldquo]genetic principles.[rdquo] Political pressure must be applied by governments and professional societies to ensure that there is not a modern reincarnation of the Soviet biological warfare program. Book Review Top Surviving cancer   p851 Bruce Zetter reviews Why Millions Survive Cancer: The Successes of Science by Lauren Pecorino doi:10.1038/nm.2766 News and Views Top Melanoma exosomes: messengers of metastasis   pp853 - 854 Rajasekharan Somasundaram and Meenhard Herlyn doi:10.1038/nm.2775 A new study shows that melanoma-derived exosomes contribute to metastatic invasion by carrying messenger proteins that direct bone marrow-derived cells toward a prometastatic phenotype. This leads to the promotion of proangiogenic events and modification of the extracellular matrix at premetastatic sites (pages 883-891). See also: Article by Peinado et al. FOXO3a and [beta]-catenin co-localization: double trouble in colon cancer?   pp854 - 856 Yibing Yan and Mark R Lackner doi:10.1038/nm.2799 Metastatic colorectal cancer is a largely incurable disease with a pressing need for targeted therapies. A new study sheds light on a surprising interaction between FOXO3a and [beta]-catenin in metastatic colorectal cancer, suggesting new therapeutic avenues for agents targeting the PI3K-AKT pathway (pages 892-901). See also: Article by Tenbaum et al. Nicotine: linking smoking to abdominal aneurysms   pp856 - 858 Koichi Sugamura and John F Keaney Jr doi:10.1038/nm.2714 The link between tobacco use and aneurysms of the abdominal aorta is well established, but the specific mechanisms involved have remained elusive for decades. A new study indicates that nicotine is the major culprit in cigarette smoke and provides a common mechanism of aneurysm formation that may allow the development of drugs to treat this disease, for which currently only surgical treatments exist (pages 902-910). See also: Article by Wang et al. Peroxiredoxin sets the brain on fire after stroke   pp858 - 859 Lidia Garcia-Bonilla and Costantino Iadecola doi:10.1038/nm.2797 How blood-borne inflammatory cells cause tissue damage in the brain after ischemic stroke remains elusive. Peroxiredoxins, cytosolic antioxidant proteins vital for redox balance, are released extracellularly from ischemic cells, acting as potent 'danger signals' that activate macrophages and lead to a harmful cytokine response, a new study shows. The findings unveil a new culprit in the delayed phase of ischemic injury and suggest new therapeutic approaches (pages 911-917). See also: Article by Shichita et al. New clues to bariatric surgery's benefits   pp860 - 861 David A Sarruf, Susan Bonner-Weir and Michael W Schwartz doi:10.1038/nm.2801 Bariatric surgery to treat obesity can also be effective against type 2 diabetes, but it is unclear how such surgical procedures improve glucose metabolism. A new study in rats suggests that nutrient sensing in the jejunum contributes to the antidiabetic effects of duodenal-jejeunal bypass (pages 950-955). See also: Letter by Breen et al. Ephrin receptor: a door to KSHV infection   pp861 - 863 Chris Boshoff doi:10.1038/nm.2803 Kaposi's sarcoma-associated herpesvirus is a major oncogenic virus that has been implicated in human cancers. A new study identifies ephrin receptor A2 as a key host receptor for this virus that permits infection of endothelial cells (pages 961-966). See also: Letter by Hahn et al. Nature Medicine JOBS of the week Postdoctoral fellow University of Texas Post Doc University of Utah at Huntsman Cancer Institute Lecturer in Chemistry (x2) University College London (UCL) Lecturer in Pharmacology The University of Liverpool Postdoc Position Vienna University of Technology (Technische Universität Wien) Sr. Equipment Maintenance Technician 2nd Shift Life Technologies PhD in cardiological research Saarland University, Institute for Molecular Cell Biology Postdoctoral Position Innate and Adaptive Immunity Against HIV University Hospital Heidelberg Tenure Track Mechanobiology of Cardiovascular Regeneration Eindhoven University of Technology (TU/e) Neurodevelopmental Basis Of Cognitive Disease, Heidelberg / Germany Heidelberg University, The Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS) More Science jobs from Nature Medicine EVENT European Society for Paediatric Endocrinology meeting (ESPE 2012) 20.-23.09.12 Leipzig, Germany More science events from Between Bedside and Bench Top The secrets of the bone marrow niche: Enigmatic niche brings challenge for HSC expansion   pp864 - 865 Yuya Kunisaki and Paul S Frenette doi:10.1038/nm.2825 The bone marrow niche keeps puzzling scientists in cancer and regenerative medicine. What elements constitute the niche and how it affects neighbor cells in different disease contexts remain to be a matter of debate and extensive investigation. The translational use of hematopoietic stem cells (HSCs) in transplantation biology poses a challenge, given the propensity of these cells to remain quiescent. Although the niche is a good candidate to exploit for reprogramming HSCs and controlling their expansion, new studies have added to its complexity. In 'Bench to Bedside', Paul S. Frenette and Yuya Kunisaki examine these studies to discuss how new players and their signals are involved in HSC maintenance and what the implications are for the development of HSC-based therapies. Among the alterations occurring in leukemias, metabolic events seem to foster cancer progression but may also be involved in cancer predisposition. Rushdia Z. Yusuf, Ying-Hua Wang and David T. Scadden peruse recent clinical and experimental studies that look at myelodysplastic syndromes and secondary leukemias and argue how metabolic changes in these cancers may not only be cell autonomous but also can emanate from the bone marrow stroma. Targeting this niche may open new avenues to reduce the risk for secondary leukemias in cancer survivors. The secrets of the bone marrow niche: Metabolic priming for AML   pp865 - 867 Rushdia Z Yusuf, Ying-Hua Wang and David T Scadden doi:10.1038/nm.2831 Research Highlights Top Neurological disorders: The pull of the prions | Immunology: Bugs tune gut defenses | Metabolic disorders: BuMPing up thermogenesis | Infectious diseases: NO means yes to Listeria infection | Bone: Autoantibodies target bone | Genetics: Somatic mutations in brain | New from NPG Review Top Taming lupus[mdash]a new understanding of pathogenesis is leading to clinical advances   pp871 - 882 Zheng Liu and Anne Davidson doi:10.1038/nm.2752 Articles Top Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET   pp883 - 891 Hector Peinado, Masa Aleckovic, Simon Lavotshkin, Irina Matei, Bruno Costa-Silva, Gema Moreno-Bueno, Marta Hergueta-Redondo, Caitlin Williams, Guillermo Garcia-Santos, Cyrus M Ghajar, Ayuko Nitadori-Hoshino, Caitlin Hoffman, Karen Badal, Benjamin A Garcia, Margaret K Callahan, Jianda Yuan, Vilma R Martins, Johan Skog, Rosandra N Kaplan, Mary S Brady, Jedd D Wolchok, Paul B Chapman, Yibin Kang, Jacqueline Bromberg and David Lyden doi:10.1038/nm.2753 Exosomes can transfer proteins and nucleic acids from one cell to another, altering the phenotype of the recipient cell. In the case of cancer, tumor-derived exosomes have been shown to promote tumor cell proliferation. Now, in a mouse model of melanoma, Peinado et al. report that exosomes derived from highly metastatic tumor cells can influence bone marrow cells, resulting in increased recruitment of provasculogenic bone marrow progenitors to sites of metastasis, increased primary tumor growth and metastatic spread. See also: News and Views by Somasundaram & Herlyn [beta]-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer   pp892 - 901 Stephan P Tenbaum, Paloma Ordonez-Moran, Isabel Puig, Irene Chicote, Oriol Arques, Stefania Landolfi, Yolanda Fernandez, Jose Raul Herance, Juan D Gispert, Leire Mendizabal, Susana Aguilar, Santiago Ramon y Cajal, Simo Schwartz Jr, Ana Vivancos, Eloy Espin, Santiago Rojas, Jose Baselga, Josep Tabernero, Alberto Munoz and Hector G Palmer doi:10.1038/nm.2772 The crosstalk between the transcriptional activity of [beta]-catenin and FOXO3a reveals unexpected pro-metastatic cooperative effects of these pathways through concurrent modulation of cell adhesion and motility programs. In tumors with high FOXO3a and [beta]-catenin activity, the proapoptotic effect of FOXO3a is subverted and the pro-proliferative effect of [beta]-catenin is also dampened, but pro-metastatic pathways are activated. These findings suggest that caution should be exerted when using targeted inhibitors that activate FOXO3a in tumors with high [beta]-catenin activity, as coactivation of both pathways also correlates with more aggressive disease in humans. See also: News and Views by Yan & Lackner Activation of AMP-activated protein kinase [alpha]2 by nicotine instigates formation of abdominal aortic aneurysms in mice in vivo    pp902 - 910 Shuangxi Wang, Cheng Zhang, Miao Zhang, Bin Liang, Huaiping Zhu, Jiyeon Lee, Benoit Viollet, Lijun Xia, Yun Zhang and Ming-Hui Zou doi:10.1038/nm.2711 Cigarette smoking raises the risk for cardiovascular disease, including the risk for abdominal aortic aneurysm. Shuangxi Wang et al. now show that nicotine itself is a causal factor in promoting abdominal aortic aneurysms in mice and delineate a pathogenic mechanism by which nicotine exposure leads to activation of the enzyme AMP-kinase in vascular smooth muscle cells and increased expression of the metallopeptidase MMP2. See also: News and Views by Sugamura & Keaney Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain   pp911 - 917 Takashi Shichita, Eiichi Hasegawa, Akihiro Kimura, Rimpei Morita, Ryota Sakaguchi, Ichiro Takada, Takashi Sekiya, Hiroaki Ooboshi, Takanari Kitazono, Toru Yanagawa, Tetsuro Ishii, Hideo Takahashi, Shuji Mori, Masahiro Nishibori, Kazumichi Kuroda, Shizuo Akira, Kensuke Miyake and Akihiko Yoshimura doi:10.1038/nm.2749 Brain cells that die after stroke release intracellular proteins into their environment. Akihiko Yoshimura and his colleagues demonstrate that peroxiredoxin proteins released from dying cells induce inflammatory cytokine expression and drive brain damage after stroke. See also: News and Views by Garcia-Bonilla & Iadecola Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue   pp918 - 925 Florian W Kiefer, Cecile Vernochet, Patrick O'Brien, Steffen Spoerl, Jonathan D Brown, Shriram Nallamshetty, Maximilian Zeyda, Thomas M Stulnig, David E Cohen, C Ronald Kahn and Jorge Plutzky doi:10.1038/nm.2757 Retinoids and their precursors are known to regulate adipose tissue maturation. Jorge Plutzky and his colleagues now show that an increased endogenous level of retinaldehyde in white adipose tissue, generated by genetic deletion of Raldh1, promotes its 'beiging' in a retinoic acid receptor-dependent manner. They also showed that genetic knockdown of Raldh1 and conversion of white to brown fat leads to weight loss and heightened glucose tolerance in obese mice in a therapeutic manner. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy   pp926 - 933 Angelika Bierhaus, Thomas Fleming, Stoyan Stoyanov, Andreas Leffler, Alexandru Babes, Cristian Neacsu, Susanne K Sauer, Mirjam Eberhardt, Martina Schnolzer, Felix Lasischka, Winfried L Neuhuber, Tatjana I Kichko, Ilze Konrade, Ralf Elvert, Walter Mier, Valdis Pirags, Ivan K Lukic, Michael Morcos, Thomas Dehmer, Naila Rabbani, Paul J Thornalley, Diane Edelstein, Carla Nau, Josephine Forbes, Per M Humpert, Markus Schwaninger, Dan Ziegler, David M Stern, Mark E Cooper, Uwe Haberkorn, Michael Brownlee, Peter W Reeh and Peter P Nawroth doi:10.1038/nm.2750 Glucose and its metabolic derivatives are increased the plasma of patients with diabetes. Peter Nawroth and colleagues demonstrate that one such metabolite, methylglyoxal, is increased in patients with painful diabetic neuropathy, and find that it acts by modifying the excitability characteristics of a sodium channel protein. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration   pp934 - 942 Zheng Sun, Russell A Miller, Rajesh T Patel, Jie Chen, Ravindra Dhir, Hong Wang, Dongyan Zhang, Mark J Graham, Terry G Unterman, Gerald I Shulman, Carole Sztalryd, Michael J Bennett, Rexford S Ahima, Morris J Birnbaum and Mitchell A Lazar doi:10.1038/nm.2744 It is believed that lipid accumulation in the liver, or fatty liver disease, contributes to insulin resistance in this organ and, thus, poorly controlled gluconeogenesis and hyperglycemia during type 2 diabetes. Mitch Lazar and colleagues now show that deletion of the chromatin modifier Hdac3 in mice results in increased fatty liver disease but improved hepatic insulin sensitivity because metabolic flux in the liver is increased toward lipid synthesis and storage and away from gluconeogenesis. NF-[kappa]B-inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action   pp943 - 949 Liang Sheng, Yingjiang Zhou, Zheng Chen, Decheng Ren, Kae Won Cho, Lin Jiang, Hong Shen, Yoshiteru Sasaki and Liangyou Rui doi:10.1038/nm.2756 Hepatic glucose production is elevated in obesity and type 2 diabetes, contributing to the hyperglycemia that occurs in these conditions. In a new study, Liangyou Rui and colleagues show that NF-[kappa]B-inducing kinase (NIK) is abnormally activated in states of obesity, resulting in elevated hepatic glucose production. When they inhibit NIK activity in the liver, hyperglycemia is lowered, suggesting NIK as a potential therapeutic target in the management of type 2 diabetes. Letters Top Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes   pp950 - 955 Danna M Breen, Brittany A Rasmussen, Andrea Kokorovic, Rennian Wang, Grace W C Cheung and Tony K T Lam doi:10.1038/nm.2745 Tony Lam and his colleagues show that the middle intestine senses glucose and has a role in a gut-brain-liver axis to regulate hepatic glucose production. They also show that an experimental form of bariatric surgery quickly ameliorates hyperglycemia in two rat models of type 1 diabetes, and the intestinal sensing of glucose they have identified probably contributes to this metabolic effect. See also: News and Views by Sarruf et al. A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target   pp956 - 960 Anjan Debnath, Derek Parsonage, Rosa M Andrade, Chen He, Eduardo R Cobo, Ken Hirata, Steven Chen, Guillermina Garcia-Rivera, Esther Orozco, Maximo B Martinez, Shamila S Gunatilleke, Amy M Barrios, Michelle R Arkin, Leslie B Poole, James H McKerrow and Sharon L Reed doi:10.1038/nm.2758 Entamoeba histolytica causes human amebiasis. Although antibiotic therapy for this infection exists, there are limited treatment options for this potentially fatal invasive disease. Anjan Debnath and colleagues now report their identification of auranofin, an approved treatment for rheumatoid arthritis, as a candidate new drug for combating E. histolytica infection. The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma-associated herpesvirus   pp961 - 966 Alexander S Hahn, Johanna K Kaufmann, Effi Wies, Elisabeth Naschberger, Julia Panteleev-Ivlev, Katharina Schmidt, Angela Holzer, Martin Schmidt, Jin Chen, Simone Konig, Armin Ensser, Jinjong Myoung, Norbert H Brockmeyer, Michael Sturzl, Bernhard Fleckenstein and Frank Neipel doi:10.1038/nm.2805 Kaposi's sarcoma-associated herpesvirus (KSHV) can infect endothelial cells, leading to the development of Kaposi's sarcoma in some individuals. The mechanisms underlying cell entry by KSHV are not fully elucidated. ahn et al. now report that ephrin receptor tyrosine kinase A2 (EphA2) acts as a cellular receptor for KSHV and show that blocking EphA2 inhibits infection of endothelial cells. See also: News and Views by Boshoff ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1   pp967 - 973 Inbal Avraham-Davidi, Yona Ely, Van N Pham, Daniel Castranova, Moshe Grunspan, Guy Malkinson, Liron Gibbs-Bar, Oded Mayseless, Gabriella Allmog, Brigid Lo, Carmen M Warren, Tom T Chen, Josette Ungos, Kameha Kidd, Kenna Shaw, Ilana Rogachev, Wuzhou Wan, Philip M Murphy, Steven A Farber, Liran Carmel, Gregory S Shelness, M Luisa Iruela-Arispe, Brant M Weinstein and Karina Yaniv doi:10.1038/nm.2759 High concentrations of some types of plasma lipoproteins, such as low-density lipoprotein, promote atherosclerosis and a wide range of vascular-related diseases. These pathogenic lipoproteins have in common the protein component apolipoprotein B. Through study of the effects of modulating lipoprotein levels in experiments involving zebrafish, mice and cultured human endothelial cells, Inbal Avraham-Davidi et al. uncover a potentially deleterious role of apolipoprotein B-containing lipoproteins as direct inhibitors of the angiogenic behavior of vascular endothelial cells. Technical Reports Top Development of a new hydrogen peroxide-based vaccine platform   pp974 - 979 Ian J Amanna, Hans-Peter Raue and Mark K Slifka doi:10.1038/nm.2763 For years, manufacturers have used one of only two chemicals to inactivate viruses for vaccine production: formaldehyde or [beta]-propiolactone, and formaldehyde can damage key antigenic epitopes, leading to reduced immunogenicity or exacerbated disease. Ian Amanna and his colleagues have now found a third, the oxidizing agent hydrogen peroxide (H2O2), which they show can be more effective than the conventional approaches. Utility of the H2O2-based approach is demonstrated in three model systems. Monoclonal TCR-redirected tumor cell killing   pp980 - 987 Nathaniel Liddy, Giovanna Bossi, Katherine J Adams, Anna Lissina, Tara M Mahon, Namir J Hassan, Jessie Gavarret, Frayne C Bianchi, Nicholas J Pumphrey, Kristin Ladell, Emma Gostick, Andrew K Sewell, Nikolai M Lissin, Naomi E Harwood, Peter E Molloy, Yi Li, Brian J Cameron, Malkit Sami, Emma E Baston, Penio T Todorov, Samantha J Paston, Rebecca E Dennis, Jane V Harper, Steve M Dunn, Rebecca Ashfield, Andy Johnson, Yvonne McGrath, Gabriela Plesa, Carl H June, Michael Kalos, David A Price, Annelise Vuidepot, Daniel D Williams, Deborah H Sutton and Bent K Jakobsen doi:10.1038/nm.2764 T cell receptor (TCR)-based immunotherapeutic approaches have so far had limited success because of a lack of specific immune recognition and activation by the TCR. Here Nathaniel Liddy and his colleagues describe the generation, optimization and characterization of a new set of reagents[mdash]immune-mobilizing monoclonal TCRs against cancer (or ImmTACs)[mdash]designed to overcome some of these limitations. The ImmTACs were used to redirect and activate T cells to lyse tumor cells both in vitro and in vivo, even those expressing very low epitope numbers on the cell surface. Top Natureevents is a fully searchable, multi-disciplinary database designed to maximise exposure for events organisers. The contents of the Natureevents Directory are now live. The digital version is available here. Find the latest scientific conferences, courses, meetings and symposia on natureevents.com. For event advertising opportunities across the Nature Publishing Group portfolio please contact natureevents@nature.com More Nature Events You have been sent this Table of Contents Alert because you have opted in to receive it. 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