Nature Medicine Contents: February 2013 Volume 19 Number 2 pp 113-246

/tr> TABLE OF CONTENTS February 2013 Volume 19, Issue 2 Podcast Editorial News Correction Book Review Correspondence News and Views Community Corner Between Bedside and Bench Research Highlights Perspectives Reviews Articles Letters Technical Reports Advertisement The Most Frequently Cited Cardiovascular and Stroke Stats Reference - the AHA/ASA 2013 Statistical Update - is now available. As your primary source, you can trust it is respected and reliable, "must know" information, which will prove enlightening and informative. When the statistics matter, the AHA/ASA Heart Disease and Stroke Statistics - 2013 Update is your source. Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement             New Nature Journals iPad app Read Nature anytime, anywhere. Subscribe to Nature on the iPad for only $35.99* Download the new app from the app store. *Apple exchange rates apply to international prices.             Nature Medicine Podcast  Top Endoscoped out  We explore a new way to image the interior lining of the esophagus and a potential biomarker for predicting who will suffer from kidney fibrosis. Listen Now Editorial Top A long pause   p113 doi:10.1038/nm.3099 Last January, scientists voluntarily imposed a pause on research that could lead to the generation of highly pathogenic avian influenza viruses with increased transmissibility to mammals. Now, new restrictions currently under debate further risk stalling progress in avian flu research. News Top Near-record number of approvals signals drug development shift   p114 Kevin Jiang doi:10.1038/nm0213-114 Ahead of WHO meeting, experts clash over tuberculosis targets   p115 Amy Maxmen doi:10.1038/nm0213-115 First 'breakthrough' drugs designated, but dilution worries linger   pp116 - 117 Elie Dolgin doi:10.1038/nm0213-116 Diagnostic lens turns to difficult-to-detect ovarian cancer   p117 Anna Azvolinsky doi:10.1038/nm0213-117 Animal rule for drug approval creates a jungle of confusion   pp118 - 119 Elie Dolgin doi:10.1038/nm0213-118 Stapled peptide to enter human testing, but affinity questions remain   p120 Yevgeniy Grigoryev doi:10.1038/nm0213-120a Amgen deal triggers watchful waiting in targeted nanomedicine   p120 Monica Heger doi:10.1038/nm0213-120b The clot thickens for long-lasting drugs that stop hemophilia short   p121 Alisa Opar doi:10.1038/nm0213-121 News in Brief Biomedical briefing   pp122 - 123 doi:10.1038/nm0213-122 Correction Top Corrections   p123 doi:10.1038/nm0213-123 News Top News Feature The Sticking Point   pp124 - 125 Elie Dolgin doi:10.1038/nm0213-124 Stitches offer a suitable means of sealing up simple wounds. But when it comes to suturing tissues inside the body, the existing methods for closing wounds fall short. Elie Dolgin meets scientists taking inspiration from nature to develop the next generation of surgical adhesives. Q&A Straight talk with...Dalvir Gill   p126 doi:10.1038/nm0213-126 In late September, ten pharmaceutical giants announced the formation of a Philadelphia-based nonprofit called TransCelerate BioPharma as a vehicle for sharing resources. This year kicked off with the appointment of its first chief executive, Dalvir Gill. He spoke with Roxanne Khamsi about his vision of how pharmaceutical firms can work together to simplify the process of multisite trials without sacrificing the quality of the data they collect. Opinion Money without collaboration won't bring cures   p127 Todd B Sherer doi:10.1038/nm0213-127 It's up to stakeholders at every stage of therapeutic development[mdash]industry and academic researchers, policymakers, patient foundations and even patients themselves[mdash]to embrace the power of collaboration. Only then will we enable translational research and push much-needed treatments to the clinic faster. Book Review Top A history of opposing reform   p128 Eric G. Campbell reviews Pills, Power, and Policy: The Struggle for Drug Reform in Cold War America and Its Consequences by Dominique A. Tobbell doi:10.1038/nm.3051 Correspondence Top Developing countries can contribute to global health innovation   p129 Justin Chakma and Hiroshi Chakma doi:10.1038/nm.3086 News and Views Top RNA editing enters the limelight in cancer   pp130 - 131 Angela Gallo doi:10.1038/nm.3072 There has been much focus on DNA mutations in tumorigenesis and tumor progression, but now a new study highlights a role for post-transcriptional changes in RNA in cancer. The authors show increased RNA editing of antizyme inhibitor 1 (AZIN1) in tumor tissues from patients with hepatocellular carcinoma and characterize a mechanism through which the expression of edited AZIN1 protein leads to increased cell proliferation (pages 209-216). See also: Article by Chen et al. Apoptosis therapy: driving cancers down the road to ruin   pp131 - 133 Douglas R. Green and Henning Walczak doi:10.1038/nm.3076 BH3 mimetics are a class of anticancer agents that hold the promise to trigger the central apoptotic machinery to set cancer cells on the road to ruin. Now, a new agent that selectively targets BCL-2, ABT-199, has been developed, with exciting preclinical and clinical results (pages 202-208). See also: Article by Souers et al. Compacting the heart with Notch   pp133 - 134 Chaitali Misra and Vidu Garg doi:10.1038/nm.3071 Left ventricular noncompaction (LVNC) cardiomyopathy is a clinically and genetically heterogeneous disease that can be associated with substantial cardiovascular morbidity and mortality. A new study shows that mice with myocardial deletion of Mib1, which encodes a ubiquitin ligase in the Notch signaling pathway, have LVNC phenotypes and identifies MIB1 mutations in humans with LVNC (pages 193-201). See also: Article by Luxan et al. Nature Medicine JOBS of the week Thermoelectric Materials Specialist National Physical Laboratory Professorship (W2) in Materials Science (Solution-Processed Semiconductors) Friedrich-Alexander-Universitat Erlangen-Nurnberg Research Fellow in Materials Science and Engineering (liver tissue engineering) Nanyang Technological University Postdoc in Thermofluids for Energy and Advanced Materials University of Toronto PhD Student for High Performance Magnetocaloric Materials DTU Energy Conversion More Science jobs from Nature Medicine EVENT Introduction to Oncology and Chemotherapy 05.22.13 New Jersey, US More science events from Community Corner Top Exploring the epigenetics of cocaine resistance   pp136 - 137 doi:10.1038/nm.3091 Between Bedside and Bench Top Weighing in on autoimmune disease: Big data tip the scale   pp138 - 139 Calliope A Dendrou, John I Bell and Lars Fugger doi:10.1038/nm.3087 Modern medicine keeps unraveling new ways to investigate autoimmunity, leading to the production of boundless amounts of genetic, cellular and imaging data. Although the precision with which this information can define the etiology and mechanisms of a particular autoimmune disease is encouraging, much work lies ahead until all the knowledge acquired can be translated into the clinic. In 'Bedside to Bench', Calliope A. Dendrou, John I. Bell and Lars Fugger discuss the promises and limitations of genome-wide and next-generation genetic studies to provide further understanding of mechanisms driving autoimmune disorders and the role of experimental medicine in the new era of integrative clinical practice and personalized medicine. In 'Bench to Bedside', Lawrence Steinman argues the concept of a 'hub and spoke' pattern of T cell activation and organ targeting in multiple sclerosis, inflammatory bowel disease and type 1 diabetes. This paradigm suggests new ways to develop drugs to keep autoreactive T cells in the organ where activation occurs and preclude them from reaching the target organ and cause disease. Weighing In On Autoimmune Disease: 'Hub-and-spoke' T cell traffic in autoimmunity   pp139 - 141 Lawrence Steinman doi:10.1038/nm.3088 Research Highlights Top Cancer: Exosomes from the stroma | Metabolism: IL-13 controls blood sugar | Pain: Painful communication | Stem cells: Promoting pluripotency Perspectives Top Harnessing CD4+ T cell responses in HIV vaccine development   pp143 - 149 Hendrik Streeck, M Patricia D'Souza, Dan R Littman and Shane Crotty doi:10.1038/nm.3054 There is renewed enthusiasm in developing an HIV vaccine and in understanding the requirements to elicit broadly neutralizing HIV-specific antibodies. In May 2012, a workshop convened researchers to discuss the interplay of CD4+ T cell and antibody responses to help identify key questions and areas of research that can inform future vaccine development. This Perspective summarizes the discussion of three main topics on the role of CD4+ T cells in HIV vaccine design. Public health challenges and prospects for malaria control and elimination   pp150 - 155 Pedro L Alonso and Marcel Tanner doi:10.1038/nm.3077 Malaria's death toll has been reduced as a result of global efforts over the last decade. Yet the rise of drug resistance and the plateauing of funding are still obstacles to eradicating the disease and reducing malaria burden. This review brings up the goals and challenges faced by researchers and the public health workforce and a way forward to effectively control and eliminate malaria. Reviews Top Malaria biology and disease pathogenesis: insights for new treatments   pp156 - 167 Louis H Miller, Hans C Ackerman, Xin-zhuan Su and Thomas E Wellems doi:10.1038/nm.3073 The potential threat of parasite resistance to current antimalarials begs further research into antimalarial drug discovery to control disease progression. In addition, even when effective drugs are used, severe malaria symptoms still pose an important risk for death and cerebral residual disease in children. Further understanding of the pathophysiology of malaria and the biology of the parasite will open doors to new antimalarial treatments. Immune mechanisms in malaria: new insights in vaccine development   pp168 - 178 Eleanor M Riley and V Ann Stewart doi:10.1038/nm.3083 WNT signaling in bone homeostasis and disease: from human mutations to treatments   pp179 - 192 Roland Baron and Michaela Kneissel doi:10.1038/nm.3074 Wnt signaling is a major regulator during development. Genetic mutations affecting main regulators of this pathway have also emphasized the relevance of Wnt signaling in bone homeostasis after birth and diseases involving bone loss and fragility, such as osteoporosis. New therapies targeting Wnt signaling to increase bone formation are now under development. Articles Top Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy   pp193 - 201 Guillermo Luxan, Jesus C Casanova, Beatriz Martinez-Poveda, Belen Prados, Gaetano D'Amato, Donal MacGrogan, Alvaro Gonzalez-Rajal, David Dobarro, Carlos Torroja, Fernando Martinez, Jose Luis Izquierdo-Garcia, Leticia Fernandez-Friera, Maria Sabater-Molina, Young-Y Kong, Gonzalo Pizarro, Borja Ibanez, Constancio Medrano, Pablo Garcia-Pavia, Juan R Gimeno, Lorenzo Monserrat, Luis J Jimenez-Borreguero and Jose Luis de la Pompa doi:10.1038/nm.3046 The Notch signaling pathway has a key role in shaping the developing heart. Guillermo Luxan et al. identify two human mutations in the gene encoding the Notch pathway protein MIB1 that cause a type of cardiomyopathy, left ventricular noncompaction. The authors show that mice lacking Mib1 in the myocardium have a similar type of cardiomyopathy and analyze how MIB1 deficiency leads to defective ventricular development. See also: News and Views by Misra & Garg ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets   pp202 - 208 Andrew J Souers, Joel D Leverson, Erwin R Boghaert, Scott L Ackler, Nathaniel D Catron, Jun Chen, Brian D Dayton, Hong Ding, Sari H Enschede, Wayne J Fairbrother, David C S Huang, Sarah G Hymowitz, Sha Jin, Seong Lin Khaw, Peter J Kovar, Lloyd T Lam, Jackie Lee, Heather L Maecker, Kennan C Marsh, Kylie D Mason, Michael J Mitten, Paul M Nimmer, Anatol Oleksijew, Chang H Park, Cheol-Min Park, Darren C Phillips, Andrew W Roberts, Deepak Sampath, John F Seymour, Morey L Smith, Gerard M Sullivan, Stephen K Tahir, Chris Tse, Michael D Wendt, Yu Xiao, John C Xue, Haichao Zhang, Rod A Humerickhouse, Saul H Rosenberg and Steven W Elmore doi:10.1038/nm.3048 Inhibition of prosurvival proteins of the BCL family is a promising anticancer strategy; however, the similarities between the family members make the development of specific agents difficult. Current compounds have been designed to target BCL-2, which is frequently elevated in tumors and is an important prosurvival factor, but also inhibit BCL-XL, which is required for the survival of platelets; thus, thrombocytopenia is a limiting toxic effect in patients. The authors have engineered anti-BCL drugs to generate a more BCL-2-specific compound that has less affinity for BCL-XL and, therefore, reduced platelet toxicity. The compound is effective in several tumor models in vivo and had reduced toxicity in three patients with refractory leukemia, showing a promising activity and safety profile to refine and improve proapoptotic therapy in cancer. See also: News and Views by Green & Walczak Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma   pp209 - 216 Leilei Chen, Yan Li, Chi Ho Lin, Tim Hon Man Chan, Raymond Kwok Kei Chow, Yangyang Song, Ming Liu, Yun-Fei Yuan, Li Fu, Kar Lok Kong, Lihua Qi, Yan Li, Na Zhang, Amy Hin Yan Tong, Dora Lai-Wan Kwong, Kwan Man, Chung Mau Lo, Si Lok, Daniel G Tenen and Xin-Yuan Guan doi:10.1038/nm.3043 RNA editing provides epigenetic diversity and is thought to be decreased in cancer. However, this report describes a phenomenon of increased RNA editing associated with malignancy in human liver tumors. The increased editing of AZIN1 is facilitated by the correlative increase in the editing enzyme ADAR1 and induces an amino acid change that leads to subcellular relocalization, increased stability and affinity for antizyme. This effect impairs antizyme's function and increases the stability of its target oncoproteins, providing protumorigenic functions. The hyperediting of AZIN1 is a protumorigenic event in liver cancer pathogenesis. See also: News and Views by Gallo Ablation of TRIP-Br2, a regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance   pp217 - 226 Chong Wee Liew, Jeremie Boucher, Jit Kong Cheong, Cecile Vernochet, Ho-Jin Koh, Cristina Mallol, Kristy Townsend, Dominique Langin, Dan Kawamori, Jiang Hu, Yu-Hua Tseng, Marc K Hellerstein, Stephen R Farmer, Laurie Goodyear, Alessandro Doria, Matthias Bluher, Stephen I-Hong Hsu and Rohit N Kulkarni doi:10.1038/nm.3056 TRIP-Br2-null mice are resistant to obesity and insulin resistance and have higher energy expenditure because of increased thermogenesis and oxidative metabolism. As expression of this transcriptional regulator is elevated in fat from obese humans, TRIP-Br2 might be a new therapeutic target against insulin resistance and hyperlipidemia. Letters Top Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis   pp227 - 231 Valerie S LeBleu, Yingqi Teng, Joyce T O'Connell, David Charytan, Gerhard A Muller, Claudia A Muller, Hikaru Sugimoto and Raghu Kalluri doi:10.1038/nm.2989 Human epididymis protein 4 (HE4), a putative serine protease inhibitor, is upregulated in human and mouse fibrotic kidneys. Inhibiting HE4 inhibited fibrosis in three different mouse models of renal disease, suggesting that HE4 is a new therapeutic target. The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity   pp232 - 237 Adam Collison, Luke Hatchwell, Nicole Verrills, Peter A B Wark, Ana Pereira de Siqueira, Melinda Tooze, Helen Carpenter, Anthony S Don, Jonathan C Morris, Nives Zimmermann, Nathan W Bartlett, Marc E Rothenberg, Sebastian L Johnston, Paul S Foster and Joerg Mattes doi:10.1038/nm.3049 Technical Reports Top Tethered capsule endomicroscopy enables less invasive imaging of gastrointestinal tract microstructure   pp238 - 240 Michalina J Gora, Jenny S Sauk, Robert W Carruth, Kevin A Gallagher, Melissa J Suter, Norman S Nishioka, Lauren E Kava, Mireille Rosenberg, Brett E Bouma and Guillermo J Tearney doi:10.1038/nm.3052 Michalina Gora and her colleagues have developed a tethered capsule endoscope in the form of a swallowable pill that does not require sedation and is the size of a one-cent coin. Once swallowed, the device was well tolerated and used to capture three-dimensional microstructural images of the digestive tract, particularly the esophagus, using optical frequency domain imaging. Feasibility was demonstrated in patients with Barrett’s esophagus, including high-grade dysplasia. Imaging local neuronal activity by monitoring PO2 transients in capillaries   pp241 - 246 Alexandre Parpaleix, Yannick Goulam Houssen and Serge Charpak doi:10.1038/nm.3059 Using a phosphorescence oxygen sensor and two-photon phosphorescence lifetime microscopy, Jerome Lecoq and his colleagues were able to map oxygen amounts in both microvascular and extravascular compartments with both high spatial and temporal resolution. The approach allowed the detection of erythrocyte-associated transients in oxygen in the rat olfactory bulb, as well as changes in tissue oxygen partial pressure (PO2) in the glomerular neuropil during odor stimulation, where a small PO2 decrease was detected before functional hyperemia. 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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