Nature Medicine Contents: November 2012 Volume 18 Number 11 pp 1593-1715

Advertisement Superior knockdown with new-generation shRNA New PLATINUM Select shRNA-mir collections are designed using shRNA-specific shERWOOD algorithm and provide unrivaled knockdown, enhanced specificity and a 100% guarantee on every shRNA-mir targeting your gene of interest. Learn more about these new collections developed at Cold Spring Harbor Laboratory and available exclusively from transOMIC technologies. TABLE OF CONTENTS November 2012 Volume 18, Issue 11 Podcast Editorial News Book Review News and Views Community Corner Between Bedside and Bench Research Highlights Perspective Brief Communication Articles Letters Technical Report Japanese table of contents Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement New Partnering Opportunities in Alzheimer's Disease! A comprehensive interactive dashboard from Relay Technology Management. Click here for more information on Alzheimer's partnering opportunities.   Advertisement 90 page eBook --- download now for free!   Published in 2012 1 E-book, 8 Medical Specialties, 43 diseases and over 200 key papers highlighted. Don't miss out, get your FREE copy of the 2012 edition of Key Advances in Medicine today!     Nature Medicine Podcast  Top Stopping a killer  Neuroscience in the age of cyborgs and a cure for the number one genetic killer of infants. Listen Now Editorial Top Toward clinical transparency   p1593 doi:10.1038/nm.3000 Big pharma has historically made some substantial missteps regarding the full reporting of clinical trial results, but a new initiative by GlaxoSmithKline is a move in the right direction. News Top Prisoners, hard hit by hepatitis C, decry lack of access to drugs   pp1594 - 1595 Cassandra Willyard doi:10.1038/nm1112-1594 Group purchasing plan launched to save on research supplies   p1595 Susan Matthews doi:10.1038/nm1112-1595 Europe plays catch-up on neonatal screening as US skips ahead   p1596 David Holmes doi:10.1038/nm1112-1596 See also: News by Dolgin Targeted vaccines against feline dander could be the cat's meow   p1597 Megan Scudellari doi:10.1038/nm1112-1597 New NIH effort seeks to find ways to make trials run smoother   p1598 Susan Matthews doi:10.1038/nm1112-1598a Spain sees worrying dip in research spending by drug companies   p1598 Michele Catanzaro doi:10.1038/nm1112-1598b Correction   p1598 doi:10.1038/nm1112-1598c Q&A Straight talk with...David Baker   p1599 doi:10.1038/nm1112-1599 In late September, the Association of University Research Parks announced that David Baker would serve as president of the organization’s board of directors for the next year and help guide its strategic goals for the next five years. Baker spoke with Roxanne Khamsi about how the organization hopes to branch out and transform these workplaces. News in Brief Biomedical briefing   pp1600 - 1601 doi:10.1038/nm1112-1600 News Features Call in the backup   pp1602 - 1606 Elie Dolgin doi:10.1038/nm1112-1602 The most common genetic killer of infants, a disease known as spinal muscular atrophy, is caused by mutations in a single gene. The human genome contains its own backup system[mdash]near-identical copies of the defective gene[mdash]yet these secondary sequences rarely get used correctly. As Elie Dolgin finds out, drug companies hope to change that, with the first wave of targeted therapies that reboot the body's backup system now entering clinical trials. Getting a fix on SMA   p1605 Elie Dolgin doi:10.1038/nm1112-1605 Opinion Clinical trials must cope better with multiplicity   p1607 Janet Wittes doi:10.1038/nm1112-1607 Clinical trials typically address more than one question. But in attempting to protect against misleading results that are due to chance when multiple interrelated tests are run simultaneously, researchers sometimes apply overly strict statistical devices that mask true effects. They should give more consideration to choosing the type of statistical analysis that fits best. Book Review Top Cocaine, Sex and Physicians   p1608 John Mendelson reviews An Anatomy of Addiction: Sigmund Freud, William Halsted, and the Miracle Drug Cocaine by Howard Markel doi:10.1038/nm.2968 News and Views Top Not just a rush of blood to the head   pp1609 - 1610 Andrew J Brumm and S Thomas Carmichael doi:10.1038/nm.2990 Angiogenesis is a key feature of central nervous system injury. A neovessel-derived signal mediated by prostacyclin triggers axonal sprouting and functional recovery in a mouse model of inflammatory spinal cord injury (pages 1658-1664). Are such angiocrine signals relevant to neurovascular remodeling and recovery in other neurological contexts? See also: Article by Muramatsu et al. SAMHD1 does it again, now in resting T cells   pp1611 - 1612 Nan Yan and Judy Lieberman doi:10.1038/nm.2980 A long-standing question in the HIV field is why HIV-1 fails to replicate in resting CD4+ T cells. A new study shows that host deoxynucleoside triphosphate triphosphohydrolase (dNTPase) sterile [alpha] motif and histidine/aspartic domain-containing protein 1 (SAMHD1), previously shown to block HIV infection in myeloid cells, also restricts HIV replication in resting CD4+ T cells by hydrolyzing dNTPs, which are needed for reverse transcription of the virus (pages 1682-1687). See also: Letter by Baldauf et al. Waking up HSCs: a new role for E-selectin   pp1613 - 1614 Malcolm A S Moore doi:10.1038/nm.2992 Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches has remained unclear. A new role in stem cell proliferation has now been identified for the adhesion molecule E-selectin expressed by bone marrow endothelial cells at the vascular niche (pages 1651-1657). See also: Book Review by FitzGerald Protective immunity from a germinal center sanctuary   pp1614 - 1616 Harriet L Robinson and Rama Rao Amara doi:10.1038/nm.2986 A new study provides mechanistic insights into how live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) can protect monkeys from infection with pathogenic SIV. The authors show that replicating LAVs stimulate a protective immune response from a safe haven in the germinal centers of lymph nodes (pages 1673-1681). See also: Article by Fukazawa et al. A sweet surprise for HIV broadly neutralizing antibodies   pp1616 - 1617 Johannes P M Langedijk and Hanneke Schuitemaker doi:10.1038/nm.2993 The production of cross-reactive neutralizing antibodies is the ultimate goal in HIV vaccine development, but no immunogen other than HIV itself has been able to elicit this type of humoral immunity. In natural HIV infections, these antibodies take several years to develop. A new study sheds light on what may be causing this delay in neutralizing antibody development (pages 1688-1692). See also: Letter by Moore et al. A sirtuin link between metabolism and heart disease   pp1617 - 1619 Keith A Webster doi:10.1038/nm.2983 The sirtuins (SIRTs) have gained preeminence for their roles in the response to caloric restriction and the regulation of aging and lifespan. A new study now identifies gene promoters that bind the transcription factor AP1 as targets for silencing by SIRT6, providing possible links between SIRT6 deficiency and dysregulation of insulin-like growth factor signaling, hypertrophic cardiomyopathy and heart failure (pages 1643-1650). See also: Article by Sundaresan et al. Small airways, big challenge: measuring the unseen?   pp1619 - 1621 Salman Siddiqui and Omar S Usmani doi:10.1038/nm.2981 An imaging technique adapted to differentiate between chronic obstructive pulmonary disease phenotypes can identify small-airway pathophysiology, locate the disease and potentially track disease progression. This approach may be used as a biomarker to identify the small-airway lesion in chronic obstructive pulmonary disease, at an individual level in the clinic (pages 1711-1715). See also: Technical Report by Galban et al. Nature Medicine JOBS of the week Post-doctoral Training Fellow Institute of Cancer Research (ICR) Postdoctoral Fellowships The Rockefeller University Staff Scientist National Institutes of Health (NIH) / Dept of Health and Human Services (DHHS) Junior Research Group Leader TU Dresden Postdoctoral position at the Pasteur Institute The Pasteur Institute Ph.D. position University of Leiden, NL Research Associate University of Manchester Postdoctoral Fellowship in Systems Neuroscience University of Michigan - Ann Arbor Postdoctoral Fellowships The Rockefeller University Assistant Professor / Associate Professor / Professor Columbia University More Science jobs from Nature Medicine EVENT Life Sciences Frontiers 22.11.12 Stockholm, Sweden More science events from Community Corner Top Defeating dengue: a challenge for a vaccine   pp1622 - 1623 doi:10.1038/nm.2997 Between Bedside and Bench Top Before Epilepsy Unfolds: Opening up the potassium door in neonatal seizures   pp1624 - 1625 Rod C Scott and Gregory L Holmes doi:10.1038/nm.2987 There is increasing interest in understanding how epilepsy initiates and how to thwart the establishment of the disease. Many questions remain open as to what targets may the best for preventing epilepsy and whether any common triggering pathway exists to treat this complex malady. In 'Bedside to Bench', Rod C. Scott and Gregory Holmes discuss alternative therapies to treat neonatal seizures to prevent chronic cognitive impairment and brain developmental problems, which can lead to epilepsy later in life. Increasing inhibitory signals in the developing brain may be useful in dampening brain hyperexcitability[mdash]and enhanced susceptibility for seizures[mdash]and blocking epilepsy development in children. In 'Bench to Bedside', Annamaria Vezzani argues how the mTOR pathway may be a potential target for blocking epileptogenesis. The role of mTOR in seizures in early life and progression of established disease raises the possibility that mTOR could be a common mediator involved in epilepsy at different stages of disease initiation and progression. Given the lack of current antiepileptic drugs to prevent seizures in children and to block epileptogenesis, developing new disease-modifying therapies remains a priority. Before Epilepsy Unfolds: Finding the epileptogenesis switch   pp1626 - 1627 Annamaria Vezzani doi:10.1038/nm.2982 Research Highlights Top Metabolism: An obesity hub | Bone: Regulating bone remodeling | Neuroscience: Growth factor can shrink reward responses | Immunology: CD8+ T cells mediate elite control | New from NPG | Autoimmunity: IL-26: inducing inflammation | Cardiovascular diseases: Degradation relieves the pressure Perspective Top Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements   pp1630 - 1638 Andrew J Holland and Don W Cleveland doi:10.1038/nm.2988 Large-scale sequencing has recently revealed the presence of highly complex, localized chromosomal rearrangements in cancer genomes. The authors discuss the evidence that such rearrangements can occur through at least two mechanisms: chromosomal shattering (chromothripsis) and template switching initiated by local defective DNA replication (chromoanasynthesis). They propose use of the term chromoanagenesis to describe this class of rearrangements, regardless of the initiating mechanism. Brief Communication Top Identification of the molecular basis of doxorubicin-induced cardiotoxicity   pp1639 - 1642 Sui Zhang, Xiaobing Liu, Tasneem Bawa-Khalfe, Long-Sheng Lu, Yi Lisa Lyu, Leroy F Liu and Edward T H Yeh doi:10.1038/nm.2919 Doxorubicin, which induces tumor cell death through effects on topoisomerase-II, is a commonly used chemotherapeutic agent but has the substantial drawback of causing cardiotoxicity. Edward T.H.Yeh and his colleagues now show that doxorubicin-induced cardiotoxicity in mice is due to the deleterious effects of doxorubicin on topoisomerase-II[beta] in cardiomyocytes, leading to alterations in gene expression, mitochondrial dysfunction and cell death. Articles Top The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun   pp1643 - 1650 Nagalingam R Sundaresan, Prabhakaran Vasudevan, Lei Zhong, Gene Kim, Sadhana Samant, Vishwas Parekh, Vinodkumar B Pillai, P V Ravindra, Madhu Gupta, Valluvan Jeevanandam, John M Cunningham, Chu-Xia Deng, David B Lombard, Raul Mostoslavsky and Mahesh P Gupta doi:10.1038/nm.2961 The chromatin-modifying protein SIRT6 has previously been shown to have anti-aging properties. Sundaresan et al. now show that SIRT6 expression is low in failing human hearts and SIRT6 in mice protects the heart by suppressing the activity of the c-Jun transcription factor, which acts as a global regulator of genes encoding components of the IGF-Akt signaling pathway. See also: News and Views by Webster Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance   pp1651 - 1657 Ingrid G Winkler, Valerie Barbier, Bianca Nowlan, Rebecca N Jacobsen, Catherine E Forristal, John T Patton, John L Magnani and Jean-Pierre Levesque doi:10.1038/nm.2969 The self renewal of hematopoietic stem cells is regulated by the bone marrow microenvironment. Whereas previous studies have focused on the role of osteoblasts, Ingrid Winkler et al. now show that bone marrow endothelial cells in the so-called 'vascular niche' contribute to this regulation by directly inducing HSC proliferation. In mice, deficiency or antagonism of the endothelial-specific adhesion protein E-selectin promotes HSC quiescence and self renewal. These findings may point to a new treatment strategy for preserving HSC function in patients undergoing chemotherapy. See also: News and Views by Moore Angiogenesis induced by CNS inflammation promotes neuronal remodeling through vessel-derived prostacyclin   pp1658 - 1664 Rieko Muramatsu, Chisato Takahashi, Shuzo Miyake, Harutoshi Fujimura, Hideki Mochizuki and Toshihide Yamashita doi:10.1038/nm.2943 Angiogenesis is induced in response to central nervous system (CNS) injury and inflammation. Toshihide Yamashita and colleagues show that in a mouse model of multiple sclerosis, new vessels form around inflammatory lesions and promote neuronal remodeling, rewiring of the corticospinal tract, and recovery of motor function in these mice. Prostacyclin is released from these vessels and promotes neuronal outgrowth by signaling through the IP receptor on neurons. See also: News and Views by Brumm & Carmichael Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways   pp1665 - 1672 Prerna Bhargava, Changlin Li, Kristopher J Stanya, David Jacobi, Lingling Dai, Sihao Liu, Matthew R Gangl, Donald A Harn and Chih-Hao Lee doi:10.1038/nm.2962 Obesity is often marked by chronic, low-grade inflammation, which is believed to contribute to metabolic disturbances associated with this condition. Chih-Hao Lee and colleagues show that injection of a known immunomodulatory glycan, one found in mother's milk and in S. mansoni egg extract, results in improved metabolic function of the adipose tissue and liver in a mouse dietary-mediated obesity model. Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines   pp1673 - 1681 Yoshinori Fukazawa, Haesun Park, Mark J Cameron, Francois Lefebvre, Richard Lum, Noel Coombes, Eisa Mahyari, Shoko I Hagen, Jin Young Bae, Marcelo Delos Reyes III, Tonya Swanson, Alfred W Legasse, Andrew Sylwester, Scott G Hansen, Andrew T Smith, Petra Stafova, Rebecca Shoemaker, Yuan Li, Kelli Oswald, Michael K Axthelm, Adrian McDermott, Guido Ferrari, David C Montefiori, Paul T Edlefsen, Michael Piatak Jr, Jeffrey D Lifson, Rafick P Sekaly and Louis J Picker doi:10.1038/nm.2934 Live attenuated SIV vaccines protect nonhuman primates from infection with pathogenic wild-type SIV, but the crucial mechanisms have not been clear. In this issue, Louis Picker and colleagues show that protection by live attenuated vaccines against intravenous SIV challenge in rhesus macaques is associated with SIV-specific T cell response in the lymph nodes, and not the blood, and persistent SIV replication in lymph node follicular T helper cells. See also: News and Views by Robinson & Amara Letters Top SAMHD1 restricts HIV-1 infection in resting CD4+ T cells   pp1682 - 1689 Hanna-Mari Baldauf, Xiaoyu Pan, Elina Erikson, Sarah Schmidt, Waaqo Daddacha, Manja Burggraf, Kristina Schenkova, Ina Ambiel, Guido Wabnitz, Thomas Gramberg, Sylvia Panitz, Egbert Flory, Nathaniel R Landau, Serkan Sertel, Frank Rutsch, Felix Lasitschka, Baek Kim, Renate Konig, Oliver T Fackler and Oliver T Keppler doi:10.1038/nm.2964 Resting CD4+ T cells are resistant to HIV-1 infection, but the underlying reasons for this lack of permissiveness have not been clear. Oliver Fackler and colleagues now report that SAMHD1, the deoxynucleoside triphosphate triphosphohydrolase responsible for restriction of HIV-1 infection in myeloid cells, also restricts infection of resting CD4+ T cells. The findings shed new light on the mechanisms of cellular and molecular regulation of HIV-1 infection. See also: News and Views by Yan & Lieberman Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape   pp1688 - 1692 Penny L Moore, Elin S Gray, C Kurt Wibmer, Jinal N Bhiman, Molati Nonyane, Daniel J Sheward, Tandile Hermanus, Shringkhala Bajimaya, Nancy L Tumba, Melissa-Rose Abrahams, Bronwen E Lambson, Nthabeleng Ranchobe, Lihua Ping, Nobubelo Ngandu, Quarraisha Abdool Karim, Salim S Abdool Karim, Ronald I Swanstrom, Michael S Seaman, Carolyn Williamson and Lynn Morris doi:10.1038/nm.2985 A minority of HIV-1-infected individuals develop broadly neutralizing antibodies, which are considered an important goal of many HIV vaccine strategies. Moore et al. now report their study of the evolution of a broadly neutralizing antibody response targeting a glycan on the viral envelope in two HIV-1-infected individuals. Their findings show that the targeted glycan is absent early in acute infection but develops over time as the virus escapes initial antibody-mediated pressure. See also: News and Views by Langedijk & Schuitemaker NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-[theta] and reactive oxygen species   pp1693 - 1698 Vincenzo Giambra, Christopher R Jenkins, Hongfang Wang, Sonya H Lam, Olena O Shevchuk, Oksana Nemirovsky, Carol Wai, Sam Gusscott, Mark Y Chiang, Jon C Aster, R Keith Humphries, Connie Eaves and Andrew P Weng doi:10.1038/nm.2960 The authors uncover a new mechanism for the regulation of the activity of leukemia-initiating cells in T-ALL. A subpopulation of stem cells with low amounts of reactive oxygen species (ROS) is enriched in their ability to reconstitute disease in mouse models, and this effect is regulated by repression of PKC-[theta], which increases ROS production. Moreover, oncogenic NOTCH, a common T-ALL-driving alteration, regulates stem cell activity by increasing RUNX3 expression, which represses RUNX1, a PCK-[theta] activator, a pathway that is conserved in human patients. PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas   pp1699 - 1704 Daniela Laimer, Helmut Dolznig, Karoline Kollmann, Paul W Vesely, Michaela Schlederer, Olaf Merkel, Ana-Iris Schiefer, Melanie R Hassler, Susi Heider, Lena Amenitsch, Christiane Thallinger, Philipp B Staber, Ingrid Simonitsch-Klupp, Matthias Artaker, Sabine Lagger, Suzanne D Turner, Stefano Pileri, Pier Paolo Piccaluga, Peter Valent, Katia Messana, Indira Landra, Thomas Weichhart, Sylvia Knapp, Medhat Shehata, Maria Todaro, Veronika Sexl, Gerald Hofler, Roberto Piva, Enzo Medico, Bruce A Ruggeri, Mangeng Cheng, Robert Eferl, Gerda Egger, Josef M Penninger, Ulrich Jaeger, Richard Moriggl, Giorgio Inghirami and Lukas Kenner doi:10.1038/nm.2966 Anaplastic large cell lymphomas (ALCL) often express the oncoprotein NPM-ALK. This study shows that the activator protein 1 family members JUN and JUNB promote lymphoma development through platelet-derived growth factor receptor-[beta] (PDGFRB). Inhibition of PDGFRB prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor against transplanted NPM-ALK tumors. Inhibition of PDGFR in a patient with ALCL also resulted in rapid, complete and sustained remission. The Toll-like receptor 5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens   pp1705 - 1710 Rhonda H Wilson, Shuichiro Maruoka, Gregory S Whitehead, Julie F Foley, Gordon P Flake, Michelle L Sever, Darryl C Zeldin, Monica Kraft, Stavros Garantziotis, Hideki Nakano and Donald N Cook doi:10.1038/nm.2920 House dust promotes allergic responses to inhaled allergens, but it remains unclear what microbial components in dust are required for this activity. Donald N. Cook and his colleagues show that the bacterial protein flagellin stimulates allergic airway responses, and its receptor, Toll-like receptor 5, is required to elicit airway eosinophilia and hyperreactivity in response to dust. Individuals with asthma have higher serum antibody titers to flagellin, suggesting exposure to flagellin is associated with allergic airway disease. Technical Report Top Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression   pp1711 - 1715 Craig J Galban, Meilan K Han, Jennifer L Boes, Komal A Chughtai, Charles R Meyer, Timothy D Johnson, Stefanie Galban, Alnawaz Rehemtulla, Ella A Kazerooni, Fernando J Martinez and Brian D Ross doi:10.1038/nm.2971 Chronic obstructive pulmonary disease (COPD) is now known to be a heterogeneous disorder, hence the pressing need to develop imaging biomarkers to differentiate between the broad range of COPD phenotypes-all of which require different treatments. Here, Craig Galban and his colleagues have adapted the parametric response map technique for the voxel-by-voxel classification analysis of CT lung images taken from a national COPD trial, providing a more objective characterization of the phenotypic contributions of functional small airways disease and emphysema in COPD. See also: News and Views by Siddiqui & Usmani 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

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