Nature Medicine Contents: July 2012 Volume 18 Number 7 pp 989-1153

TABLE OF CONTENTS July 2012 Volume 18, Issue 7 Podcast Editorial News Correction Book Review News and Views Community Corner Between Bedside and Bench Research Highlights Reviews Articles Letters Technical Reports Japanese table of contents Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Biostatistician With a Medical career at Saudi Aramco, a global leader in the energy industry, you'll work in a state-of-the-art facility that prides itself on the very highest standards of clinical excellence. What's more, you'll practice alongside an expert peer group in an environment that allows you to do what you do best. www.jobsataramco.eu/naturebiojp uncommon opportunities   Advertisement Scientific Reports publishes 457 open access papers in its first year Publishing technically sound research articles, Scientific Reports is Nature Publishing Group’s fastest growing journal. Given the speed and visibility offered, no wonder 93% of our authors said that they are “likely” or “very likely” to submit again. Keep your research moving. Submit to Scientific Reports   Advertisement Nature Medicine and the Volkswagen Foundation present: Herrenhausen Symposium on Metastasis October 8-10, 2012 - Seeon, Germany A subset of leaders in the field will attend the Herrenhausen Symposium and participate in an interdisciplinary discussion that will point in the direction of solutions to the greatest challenges that the field of viral pathogenesis faces. Application deadline is July 10th Apply today!   Nature Medicine Podcast  Top Strike a cord  A robotic device helps rats recover from spinal cord injury and a biodegradable material offers a new way to make artery grafts. Listen Now Editorial Top Learning to share   p989 doi:10.1038/nm.2880 Biomedical research faces budgetary cuts in the United States and abroad. But although solutions to manage the restricted funds can be found, initiating change may be the greater hurdle. News Top 'Must-pass' FDA fee renewal jammed with sunscreen and more   p990 Chase Scheinbaum doi:10.1038/nm0712-990 New adjuvants aim to give whooping cough vaccine a boost   p991 Melinda Wenner Moyer doi:10.1038/nm0712-991a Accord could make Canadian generics industry a 'rust bucket'   p991 Hannah Hoag doi:10.1038/nm0712-991b Biobanks look to software solutions to handle data deluge   p992 Anna Petherick doi:10.1038/nm0712-992a First therapy targeting Parkinson's proteins enters clinical trials   pp992 - 993 Elie Dolgin doi:10.1038/nm0712-992b Cancer immunotherapy shows promise in multiple tumor types   p993 Monica Heger doi:10.1038/nm0712-993 News in Brief Biomedical briefing   pp994 - 995 doi:10.1038/nm0712-994 Correction Top Corrections   p995 doi:10.1038/nm0712-995 News Top New class of sleep drugs may offer a safer night's rest   p996 Cassandra Willyard doi:10.1038/nm0712-996 Focus on sepsis   p997 doi:10.1038/nm0712-997 Rodent models of sepsis found shockingly lacking   p998 Kathleen Raven doi:10.1038/nm0712-998a Execution of sepsis trials needs an overhaul, experts say   pp998 - 999 Roxanne Khamsi doi:10.1038/nm0712-998b New biomarkers sought for improving sepsis management and care   p999 Melinda Wenner Moyer doi:10.1038/nm0712-999 Trial failure prompts soul-searching for critical-care specialists   p1000 Elie Dolgin doi:10.1038/nm0712-1000 After Xigris, researchers look to new targets to combat sepsis   p1001 Sarah C P Williams doi:10.1038/nm0712-1001 Q&A Straight talk with...Phillip Dellinger   p1002 doi:10.1038/nm0712-1002 Since its inception ten years ago, the Surviving Sepsis Campaign has successfully developed a series of best-practice criteria—the International Guidelines on theManagement of Severe Sepsis and Septic Shock, which are currently being revised under Phillip Dellinger’s leadership—as well as engaged physicians and the general public around the world in a broad educational program to warn about the threat posed by the disease. Dellinger spoke with Roxanne Khamsi about the struggle to catalyze change in the sepsis field. News Feature To serve and neuroprotect   pp1003 - 1006 Elie Dolgin doi:10.1038/nm0712-1003 Drugs designed to protect or rescue neurons from damage wrought by stroke have repeatedly failed in clinical trials, prompting a mass flight of pharmaceutical companies from the field. A small Canadian startup is bucking the trend[mdash]and it hopes that monkey data will help the field evolve. Elie Dolgin reports. Opinion Refocus the Recombinant DNA Advisory Committee   p1007 Xandra O Breakefield doi:10.1038/nm0712-1007 The Recombinant DNA Advisory Committee, formed in 1974, was originally charged with advising on potential risks of recombinant technology and took on review of clinical gene therapy protocols in the late 1980s. But as gene therapy has made headway with safety, it's time to shift the committee's mission toward broader ethical and technical issues linked to the field. Book Review Top Mission against malaria   p1008 Mats Wahlgren reviews Lifeblood: How to Change the World One Dead Mosquito at a Time by Alex Perry doi:10.1038/nm.2774 News and Views Top MiR-23b is a safeguard against autoimmunity   pp1009 - 1010 Ruozhen Hu and Ryan M O'Connell doi:10.1038/nm.2849 MicroRNAs (miRNAs) have emerged as crucial mediators of human disease, but their roles in autoimmunity have only recently been appreciated. A new study using mouse and human tissues from various interleukin-17 (IL-17)-related autoimmune disorders now shows that miRNA-23b is a central regulator of inflammation in resident tissue cells during autoimmunity (pages 1077-1086). See also: Article by Zhu et al. Co-opting endogenous microRNAs for therapy   pp1011 - 1012 Christopher E Pearson doi:10.1038/nm.2864 A recent study highlights the potential of therapeutically modulating the endogenous miRNA pathway in a mouse model of spinal and bulbar muscular atrophy (SBMA). The overexpression of a naturally occurring miRNA led to the downregulation of the mutant androgen receptor transcript as well as the polyglutamine-containing protein it encodes, both of which may contribute to pathogenesis in SBMA (pages 1136-1141). See also: Letter by Miyazaki et al. To survive radiation injury, remember your aPCs   pp1013 - 1014 John P Chute doi:10.1038/nm.2859 Acute exposure to ionizing radiation can cause lethality via severe damage to the hematopoietic system. A new study shows that infusion of the anticoagulants thrombomodulin or activated protein C reduces radiation toxicities and improves survival (pages 1123-1129). See also: Letter by Geiger et al. NKT cells[mdash]an early warning system for HBV infection   pp1014 - 1016 Dale I Godfrey, Adam P Uldrich and Alan G Baxter doi:10.1038/nm.2853 Whereas the adaptive immune response is essential for control and clearance of hepatitis B virus infection, the importance of the early innate immune response is controversial and the players involved are poorly defined. A new study shows that activation of natural killer T cells by infected hepatocytes is crucial for the early control of this disease (pages 1060-1068). See also: Article by Zeissig et al. Cutting SRC-1 down to size in endometriosis   pp1016 - 1018 Matthew T Dyson and Serdar E Bulun doi:10.1038/nm.2855 Endometriosis occurs when estrogen-sensitive endometrial cells that are shed to distal sites manage to attach and survive in a foreign, inflammatory environment. A new study reports a unique interaction between a cleaved form of steroid receptor coactivator 1 (SRC-1) and caspase 8 that blocks apoptosis in endometriotic cells, allowing them to survive (pages 1102-1111). See also: Article by Han et al. Primed for inflammation: enthesis-resident T cells   pp1018 - 1019 Rik J Lories and Iain B McInnes doi:10.1038/nm.2854 The enthesis is the region at the junction between tendon and bone and has been suggested to be a key target in spondyloarthritic diseases. This zone is now shown to contain a unique population of resident T cells, which, when activated by the cytokine interleukin-23 (IL-23), can promote pathogenesis that is characteristic of spondyloarthritis (pages 1069-1076). See also: Article by Sherlock et al. Nature Medicine JOBS of the week PhD-position in Bioinformatics with a focus on Microbial Forensics and Population Genetics Umea University Post-Doctoral Research Fellowships 2013-18 All Souls College, University of Oxford Research Associate Vertex Postdoctoral position: membrane fusion imaging Institute of Anatomy, Medical Faculty, University of Bern Assistant Professor in Physical Chemistry Middlebury College Fellowships in Regulatory Affairs - Chemistry, Manufacturing , and Controls (CMC) / Manufacturing Sciences Biogen Idec Breast Cancer Postdoctoral Fellow Albert Einstein College of Medicine Postdoctoral Fellow The LSU Health– New Orleans, Sciences Center Postdoctoral Fellowship Northwestern Univeristy Feinberg School of Medicine Research Technician King's College London More Science jobs from Nature Medicine EVENT Photocontrol and Optogenetic of Biological Systems and Functions 17.-20.09.12 Paris, France More science events from Community Corner Top Mining the mechanisms of an HIV vaccine   pp1020 - 1021 doi:10.1038/nm.2858 Between Bedside and Bench Top Untuning the tumor metabolic machine: Targeting cancer metabolism: a bedside lesson   pp1022 - 1023 Kivanc Birsoy, David M Sabatini and Richard Possemato doi:10.1038/nm.2870 Several decades of scientific observations followed by years of basic and now clinical research support the notion that the metabolic power of tumor cells can provide the long-desired Achilles' heel of cancer. Yet many questions remain as to what defines the true metabolic makeup of a tumor and whether well-known factors and pathways involved in metabolic signaling act as tumor suppressors or oncogenes. In 'Bedside to Bench', Kivanc Birsoy, David M. Sabatini and Richard Possemato discuss how retrospective studies of diabetic individuals with pancreatic cancer treated with the antidiabetic drug metformin point to a possible anticancer effect for this drug. Further research will need to discern whether this drug acts at the organismal level or by directly targeting the power plant of tumor cells. In 'Bench to Bedside', Regina M. Young and M. Celeste Simon peruse the complex function of a key metabolic factor that mediates the cell's response to low oxygen levels, often found in tumors. This hypoxia-inducible factor (HIF) comes in two flavors, which can be either tumor promoting or tumor suppressive, depending on the type of cancer. Because of this, the therapeutic use of HIF inhibitors must proceed with caution. Further defining the relationship between metabolic regulation of HIF and tumor progression may open up new diagnostic tools and treatments. Untuning the tumor metabolic machine: HIF-[alpha]: pro- and antitumorigenic?   pp1024 - 1025 Regina M Young and M Celeste Simon doi:10.1038/nm.2865 Research Highlights Top Cancer: Notch plays the skin field | Cancer: p53 functions under scrutiny | Microbiology: Friendly fungi | Immunology: Unexpected effects | Metabolic disorders: A route to leanness | Infectious diseases: Turning the tide against TB | New from NPG Reviews Top Mechanisms of fibrosis: therapeutic translation for fibrotic disease   pp1028 - 1040 Thomas A Wynn and Thirumalai R Ramalingam doi:10.1038/nm.2807 Fibrosis is a key aspect of many chronic inflammatory diseases and can affect almost every tissue in the body. This review discusses recent advances in our understanding of the mechanisms of fibrosis, focusing on the innate and adaptive immune responses. It also describes how some of these crucial pathogenic pathways are being therapeutically targeted in the clinic. From prenatal genomic diagnosis to fetal personalized medicine: progress and challenges   pp1041 - 1051 Diana W Bianchi doi:10.1038/nm.2829 Genomic technologies are being rapidly applied to the area of prenatal diagnosis, and many genomic prenatal tests have already been transitioned to the clinic. Diana Bianchi reviews these advances in prentatal diagnosis and highlights the challenges in bringing them to the clinic. She also discusses how genomic and transcriptomic technologies might be applied to understand the pathology of fetal diseases and disorders of pregnancy and, perhaps, develop new therapies for these conditions. Articles Top Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance   pp1052 - 1059 Justin M Balko, Rebecca S Cook, David B Vaught, Maria G Kuba, Todd W Miller, Neil E Bhola, Melinda E Sanders, Nara M Granja-Ingram, J Joshua Smith, Ingrid M Meszoely, Janine Salter, Mitch Dowsett, Katherine Stemke-Hale, Ana M Gonzalez-Angulo, Gordon B Mills, Joseph A Pinto, Henry L Gomez and Carlos L Arteaga doi:10.1038/nm.2795 By digital profiling of residual breast tumors after neoadjuvant therapy, the authors identify gene expression patterns that correspond with a higher risk of metastasis and recurrence. Activation of the Ras-ERK pathway through loss of DUSP4 confers therapy resistance that can be overcome by combined treatment with MEK inhibitors. Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity   pp1060 - 1068 Sebastian Zeissig, Kazumoto Murata, Lindsay Sweet, Jean Publicover, Zongyi Hu, Arthur Kaser, Esther Bosse, Jahangir Iqbal, M Mahmood Hussain, Katharina Balschun, Christoph Rocken, Alexander Arlt, Rainer Gunther, Jochen Hampe, Stefan Schreiber, Jody L Baron, D Branch Moody, T Jake Liang and Richard S Blumberg doi:10.1038/nm.2811 Hepatitis B virus (HBV) infection is known to be controlled by T and B cell responses, but the role of natural killer T (NKT) cells is less clear. Richard Blumberg and his colleagues now show that NKT cells are activated immediately after HBV infection by presentation of an HBV-altered repertoire of lysophospholipids on infected hepatocytes and are necessary for the induction of optimal T and B cell responses and rapid viral control. See also: News and Views by Godfrey et al. IL-23 induces spondyloarthropathy by acting on ROR-[gamma]t+ CD3+CD4-CD8- entheseal resident T cells   pp1069 - 1076 Jonathan P Sherlock, Barbara Joyce-Shaikh, Scott P Turner, Cheng-Chi Chao, Manjiri Sathe, Jeff Grein, Daniel M Gorman, Edward P Bowman, Terrill K McClanahan, Jennifer H Yearley, Gerard Eberl, Christopher D Buckley, Robert A Kastelein, Robert H Pierce, Drake M LaFace and Daniel J Cua doi:10.1038/nm.2817 Spondyloarthropathies are characterized by a distinct pattern of inflammation at distinct anatomical sites and are associated with elevated expression of interleukin 23 (IL-23). Daniel Cua and his colleagues identify an IL-23-responsive CD4-CD8- T cell population located within entheses. Systemic overexpression of IL-23 activates these cells and recapitulates aspects of the human disease in mice, and neutralization of IL-17 and IL-22 decreases pathology, suggesting new therapeutic targets for these disorders. See also: News and Views by Lories & McInnes The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-[alpha]   pp1077 - 1086 Shu Zhu, Wen Pan, Xinyang Song, Yan Liu, Xinrui Shao, Yuanjia Tang, Dong Liang, Dongyi He, Honglin Wang, Wenjun Liu, Yufang Shi, John B Harley, Nan Shen and Youcun Qian doi:10.1038/nm.2815 Several microRNAs have been identified that affect lymphocyte effector function and contribute to autoimmune inflammatory disease. Here Youcun Qian and his colleagues find that interleukin-17 (IL-17) suppresses miR-23b expression in nonimmune cells present in inflammatory lesions from individuals with rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis and in the respective mouse models. MiR-23b targets several signaling molecules downstream of IL-17, TNF-[alpha] and IL-1[beta] signaling, thereby suppressing proinflammatory cytokine expression and inhibitng autoimmune pathogenesis in vivo. See also: News and Views by Hu & O'Connell Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects   pp1087 - 1094 Eva M Jimenez-Mateos, Tobias Engel, Paula Merino-Serrais, Ross C McKiernan, Katsuhiro Tanaka, Genshin Mouri, Takanori Sano, Colm O'Tuathaigh, John L Waddington, Suzanne Prenter, Norman Delanty, Michael A Farrell, Donncha F O'Brien, Ronan M Conroy, Raymond L Stallings, Javier DeFelipe and David C Henshall doi:10.1038/nm.2834 Temporal lobe epilepsy (TLE) is linked to neuron death in the hippocampus. Now David Henshall and colleagues show that miR-134 is upregulated in humans with TLE and in an experimental epilepsy model in mice. Decreasing miR-134 before induction of epilepsy in mice reduces neuron death and the generation of spontaneous seizures. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells   pp1095 - 1101 Lingling Xian, Xiangwei Wu, Lijuan Pang, Michael Lou, Clifford J Rosen, Tao Qiu, Janet Crane, Frank Frassica, Liming Zhang, Juan Pablo Rodriguez, Xiaofeng Jia, Shoshana Yakar, Shouhong Xuan, Argiris Efstratiadis, Mei Wan and Xu Cao doi:10.1038/nm.2793 Bone remodeling involves a coupled balance between bone resorption and bone formation. Xu Cao and his colleagues have shown before that mesenchymal stem cells (MSCs) are recruited to the surface of the bone during this process. They now show that insulin-like growth factor 1 (IGF-1) is released from the bone surface during bone resorption, where it signals the recruited MSCs to differentiate into osteoblasts. In this way, bone resorption is linked to bone formation, and IGF-1 as a target of bone therapy is suggested. A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis   pp1102 - 1111 Sang Jun Han, Shannon M Hawkins, Khurshida Begum, Sung Yun Jung, Ertug Kovanci, Jun Qin, John P Lydon, Francesco J DeMayo and Bert W O'Malley doi:10.1038/nm.2826 Endometriosis afflicts ~15% of women of reproductive age, causing pelvic pain, and is often associated with infertility. In a new study, Bert O'Malley and his colleagues now show that in response to TNF-[alpha] signaling, a unique isoform of SRC-1, an estrogen receptor coactivator, is elevated in endometriotic tissue, preventing the normal apoptosis of these cells. These results could explain the proliferation of these cells, while also further suggesting the antibody to TNF-[alpha] etanercept as a therapy for this condition. See also: News and Views by Dyson & Bulun Letters Top Activation of the epithelial Na+ channel triggers prostaglandin E2 release and production required for embryo implantation   pp1112 - 1117 Ye Chun Ruan, Jing Hui Guo, Xinmei Liu, Runju Zhang, Lai Ling Tsang, Jian Da Dong, Hui Chen, Mei Kuen Yu, Xiaohua Jiang, Xiao Hu Zhang, Kin Lam Fok, Yiu Wa Chung, Hefeng Huang, Wen Liang Zhou and Hsiao Chang Chan doi:10.1038/nm.2771 Activation of the epithelial Na+ channel ENaC in mouse endometrium triggers Ca2+ influx and upregulation of cyclooxygenase 2, an enzyme key for prostaglandin production and for embryo implantation. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia   pp1118 - 1122 Alex Kentsis, Casie Reed, Kim L Rice, Takaomi Sanda, Scott J Rodig, Eleni Tholouli, Amanda Christie, Peter J M Valk, Ruud Delwel, Vu Ngo, Jeffery L Kutok, Suzanne E Dahlberg, Lisa A Moreau, Richard J Byers, James G Christensen, George Vande Woude, Jonathan D Licht, Andrew L Kung, Louis M Staudt and A Thomas Look doi:10.1038/nm.2819 This report identifies upregulation of HGF as an autocrine growth pathway in several subsets of AML. Ligand-dependent activation of MET represents a new oncogenic stimulus, and the dynamic regulation of HGF can overcome the effects of MET inhibition. These results suggest that combination treatments may be needed to disrupt this autocrine signaling loop and quell the growth of AML. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity   pp1123 - 1129 Hartmut Geiger, Snehalata A Pawar, Edward J Kerschen, Kalpana J Nattamai, Irene Hernandez, Hai Po H Liang, Jose A Fernandez, Jose A Cancelas, Marnie A Ryan, Olga Kustikova, Axel Schambach, Qiang Fu, Junru Wang, Louis M Fink, Karl-Uwe Petersen, Daohong Zhou, John H Griffin, Christopher Baum, Hartmut Weiler and Martin Hauer-Jensen doi:10.1038/nm.2813 Using an unbiased genetic screen in mice, Hartmut Geiger et al. found that the thrombomodulin-activated protein C pathway, which controls blood coagulation among other functions, also protects from radiation damage. Administration of a recombinant variant of thrombomodulin or of recombinant activated protein C protected mice from total body irradiation, pointing to potential therapeutic applications. See also: News and Views by Chute Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet   pp1130 - 1135 Gesine Saher, Fabian Rudolphi, Kristina Corthals, Torben Ruhwedel, Karl-Friedrich Schmidt, Siegrid Lowel, Payam Dibaj, Benoit Barrette, Wiebke Mobius and Klaus-Armin Nave doi:10.1038/nm.2833 Pelizaeus-Merzbacher disease (PMD) is a neurological disease caused by loss of myelin. Now, Gesine Saher et al. show that a cholesterol-enriched diet can ameliorate disease in a mouse model of PMD. Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2   pp1136 - 1141 Yu Miyazaki, Hiroaki Adachi, Masahisa Katsuno, Makoto Minamiyama, Yue-Mei Jiang, Zhe Huang, Hideki Doi, Shinjiro Matsumoto, Naohide Kondo, Madoka Iida, Genki Tohnai, Fumiaki Tanaka, Shin-ichi Muramatsu and Gen Sobue doi:10.1038/nm.2791 Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by aggregation of the androgen receptor (AR) protein. Here Gen Sobue and colleagues show that upregulation of miR-196a can reduce expression of AR mRNA and ameliorate disease symptoms in mouse models of SBMA. See also: News and Views by Pearson Technical Reports Top Versatile robotic interface to evaluate, enable and train locomotion and balance after neuromotor disorders   pp1142 - 1147 Nadia Dominici, Urs Keller, Heike Vallery, Lucia Friedli, Rubia van den Brand, Michelle L Starkey, Pavel Musienko, Robert Riener and Gregoire Courtine doi:10.1038/nm.2845 Nadia Dominici and her colleagues have developed a multidirectional robotic neurorehabilitation system that is capable of operating as a propulsive or postural neuroprosthesis and overcomes some of the limitations of existing systems. The robotic interface allows for the independent assessment and restoration of motor function in rats with mild to severe neuromotor disorders and is validated in various models of spinal cord injury and stroke. Fast-degrading elastomer enables rapid remodeling of a cell-free synthetic graft into a neoartery   pp1148 - 1153 Wei Wu, Robert A Allen and Yadong Wang doi:10.1038/nm.2821 In the past, small-diameter, synthetic vascular prostheses have been made in vitro either entirely from cells or by inoculating cells onto scaffolds. Wei Wu and colleagues have taken a cell-free approach where biodegradable elastomeric grafts are rapidly degraded, producing neoarteries that were almost free of foreign materials 90 days after grafting in a rat abdominal aorta. Grafts were rapidly remodeled by the host and produced compliance and burst pressure values similar to those of native aorta. 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. 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