Nature Medicine Contents: June 2013 Volume 19 Number 6 pp 653-790

Advertisement 2014 Vilcek Prizes for Creative Promise The Vilcek Foundation is seeking young, foreign-born biomedical scientists with drive, talent, and ingenuity 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. TABLE OF CONTENTS June 2013 Volume 19, Issue 6 Podcast Editorial News Book Review News and Views Community Corner Between Bedside and Bench Research Highlights Perspective Articles Letters Technical Reports Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Mitochondrial Disease: Translating biology into new treatments (2-4 October 2013) Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. This exciting new Wellcome Trust conference will bring together world leaders in the field of translational mitochondrial medicine. Abstracts due 16 Jul. Register by 20 August.   Advertisement Wondering where to publish your next paper? Frontiers is a community-oriented open-access publisher and research network. We are driving innovations around peer-review and a whole ecosystem of open science tools Be a part of the future of research publication   Advertisement UCSD Clinical and Translational Research Institute and Nature Medicine present: Bench to Bedside 2013: Cancer Therapeutics November 4-6, 2013 Estancia La Jolla Hotel La Jolla, CA, USA Click here or more information or to register for this conference today!   Nature Medicine Podcast  Top Glucagon away Scientists show that the glucagon hormone acts in the brain, and a biosecurity center takes on a new identity. Listen Now Editorial Top Sticker shock   p653 doi:10.1038/nm.3244 A recent plea by oncologists condemning inflated prices for some cancer drugs has ignited a debate on this topic between clinicians and pharmaceutical companies and highlights the need for a broader assessment of drug valuation. News Top Charged by GSK investment, battery of electroceuticals advance   p654 Gunjan Sinha doi:10.1038/nm0613-654 'Basket studies' will hold intricate data for cancer drug approvals   p655 Cassandra Willyard doi:10.1038/nm0613-655 Heavy drugs draw heavy interest from pharma backers   p656 Alla Katsnelson doi:10.1038/nm0613-656 Q&A Straight talk with...Tom Inglesby   p657 doi:10.1038/nm0613-657 The Center for Biosecurity of the University of Pittsburgh Medical Center (UPMC) was recently renamed the UPMC Center for Health Security. As director and chief executive officer for the past four years, Tom Inglesby has expanded the center’s focus toward preventing public health crises arising from infectious diseases, pandemics and major natural disasters, in addition to biological, chemical and nuclear accidents or threats. Inglesby spoke with Kevin Jiang about how responses to bioterrorism, pandemics and natural disasters aren’t all that different. News in Brief Biomedical briefing   pp658 - 659 doi:10.1038/nm0613-658 News Feature Cancer's true breackthroughs   pp660 - 663 Elie Dolgin doi:10.1038/nm.3245 A new regulatory pathway established last year allows drugs with dramatic early clinical promise to be expedited to the market quicker than ever before. To date, most of these 'breakthrough' designations have gone to cancer agents, raising the prospect of faster access to the latest lifesaving therapies for the estimated 4,500 people newly diagnosed with cancer each day in the US. Elie Dolgin looks at what sets these breakthrough medicines apart. Opinion An updated Declaration of Helsinki will provide more protection    p664 Cecil B. Wilson doi:10.1038/nm0613-664 Almost 50 years ago, the World Medical Association adopted the Declaration of Helsinki as an ethical guide for research involving human subjects. There are now proposed revisions under consideration that will provide additional protection for study participants as well as increased clarity regarding the responsibilities of those conducting the research. Making these changes is important in a complex environment where what is ethical is not always self-evident. Book Review Top Getting personal with cancer   p665 Neil P Shah reviews The Philadelphia Chromosome: A Mutant Gene and the Quest to Cure Cancer at the Genetic Level by Jessica Wapner doi:10.1038/nm.3199 News and Views Top Nitric oxide quenches the fire in heart mitochondria   pp666 - 667 Paul T Schumacker doi:10.1038/nm.3224 During resuscitation after cardiac arrest, a burst of reactive oxygen species (ROS) generated in mitochondria triggers a lethal cascade of events. Nitric oxide is known to be protective, but the mechanism is unknown. A new study shows that a mitochondria-targeted nitric oxide donor S-nitrosates the ND3 subunit of mitochondrial complex I, limiting its ability to generate ROS and protecting the heart against injury (pages 753-759). See also: Letter by Chouchani et al. TGF-β and osteoarthritis—the good and the bad   pp667 - 669 Jason R Bush and Frank Beier doi:10.1038/nm.3228 Blockage of transforming growth factor-β (TGF-β) signaling in subchondral bone after acute injury in rodents prevents aberrant bone remodeling and cartilage degeneration, suggesting that TGF-β signaling in bone may initiate osteoarthritis in some cases (pages 704-712). See also: Article by Zhen et al. It takes nerves to recover from chemotherapy   pp669 - 671 Jean-Pierre Levesque and Ingrid G Winkler doi:10.1038/nm.3231 Anticancer cytotoxic drugs also kill normal progenitors found in rapidly regenerating tissues, resulting in prolonged hematopoietic insufficiency. Chemotherapy-induced toxicity of the nerves that regulate bone marrow niches required for regeneration of hematopoietic stem cells (HSCs) is involved in this insufficiency, which suggests that co-administration of neuroprotective agents may protect HSCs from the toxic effects of drugs such as cisplatin and vincristine (pages 695-703). See also: News and Views by Levesque & Winkler How the antiviral immune response boosts liver fat   pp671 - 672 Gregory Camus and Melanie Ott doi:10.1038/nm.3226 Liver steatosis is a characteristic feature of hepatitis C virus (HCV) infection, and the virus itself is known to alter the lipid metabolism of infected hepatocytes. A recent study shows that HCV co-opts the antiviral innate immune response to stimulate the production of hepatic fat droplets, which it can then use to complete its own life cycle and spread (pages 722-729). See also: Article by Li et al. Mast cells fuel the fire of malaria immunopathology   pp672 - 674 Christian R Engwerda and Rajiv Kumar doi:10.1038/nm.3227 Malaria remains the most deadly human parasitic disease. A new study finds that malaria parasites signal to mast cells to promote disease through the expansion of specialist dendritic cells and the subsequent activation of pathogenic CD8+ T cells (pages 730-738). See also: Article by Guermonprez et al. Glucagon's yin and yang effects on hepatic glucose production   pp674 - 675 Dale S Edgerton and Alan D Cherrington doi:10.1038/nm.3202 New insights into the actions of the hormone glucagon are provided by a recent study in rodents, which shows that glucagon can suppress hepatic glucose production by acting through the mediobasal hypothalamic region of the brain. This central regulatory mechanism is impaired in rats fed a high-fat diet, suggesting that hypothalamic glucagon resistance may be relevant to the hyperglycemia observed in obesity, diabetes or both (pages 766-772). See also: Article by Lucas et al. Nature Medicine JOBS of the week Postdoctoral Research Associate University of Reading Lecturer / Senior Lecturer in Physiology King's College London Pharmacology and Toxicology University of Toronto Department of Pharmacology and Toxicology Postdoctoral Researcher / Senior Postdoctoral Researcher Louisiana State University (LSU) More Science jobs from Nature Medicine EVENT qPCR & Digital PCR Congress 09.-10.09.13 Lyon, France More science events from Community Corner Top Tracking tumor resistance using 'liquid biopsies'   pp676 - 677 doi:10.1038/nm.3233 Between Bedside and Bench Top Treating the Brain Deep Down: Brain surgery for anorexia nervosa?   pp678 - 679 Eric J Nestler doi:10.1038/nm.3223 Using brain surgery, specific areas in the brain can be stimulated with electrical impulses to reversibly change their activity and alleviate symptoms related to mental illnesses. This so-called deep brain stimulation and other methodological advances that even more selectively activate specific groups of neurons can give us clues as to what neural circuitry is involved in a particular mental disorder and whether therapeutic activation of these brain areas and neurons may be effective. In 'Bedside to Bench', Eric Nestler discusses two trials of individuals with anorexia nervosa in which deep brain stimulation of different brain areas resulted in improvement of behavioral domains associated with the syndrome. The results and potential of this technique in animals and humans may bring us closer to understanding the neurobiology of anorexia nervosa, which still remains a mystery and poses a challenge for treatment. In 'Bench to Bedside', Jennifer Warner-Schmidt peruses recent findings that uncover the functional connectivity of brain regions involved in depression and how activation of cortical regions can result in antidepressant effects that can compensate for the malfunction of other brain circuits that results in depression. Treating the Brain Deep Down: Short-circuiting depression   pp680 - 681 Jennifer Warner-Schmidt doi:10.1038/nm.3215 Research Highlights Top Cancer: Enhancing EGFR targeting | Autism spectrum disorders: Mutual mutation mechanisms | Cardiovascular diseases: Young blood helps the heart | Neurodevelopmental disorders: A therapy for Pretzel syndrome | Aging: A new target in progeria | New from NPG | Malaria: Malaria network using vesicles | Immunology: Restraining natural killer cells Perspective Top Progress toward treatments for synaptic defects in autism   pp685 - 694 Richard Delorme, Elodie Ey, Roberto Toro, Marion Leboyer, Christopher Gillberg and Thomas Bourgeron doi:10.1038/nm.3193 Autism spectrum disorders (ASDs) are a clinically heterogeneous group of neurodevelopmental disorders characterized by social and communication deficits and repetitive behaviors. In a subset of individuals with ASD, mutations in genes involved in synaptic function have been identified, and this Perspective discusses the evidence from mouse models of ASD that synaptic deficits can be ameliorated in the mature brain. The authors also suggest a strategy for designing more informative clinical trials for ASD therapies that stratify patients according to their specific synaptic mutations. Articles Top Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration   pp695 - 703 Daniel Lucas, Christoph Scheiermann, Andrew Chow, Yuya Kunisaki, Ingmar Bruns, Colleen Barrick, Lino Tessarollo and Paul S Frenette doi:10.1038/nm.3155 Many chemotherapy drugs cause sensory nerve damage as well as long-lasting damage to hematopoietic regeneration in the bone marrow. Paul Frenette and his colleagues show that this hematopoietic damage is caused by injury to bone marrow sympathetic nerve fibers, disrupting the hematopoietic stem cell niche. These findings point to the potential of neuroprotective agents in preserving hematopoietic function in chemotherapy-treated patients with cancer. See also: News and Views by Levesque & Winkler Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis   pp704 - 712 Gehua Zhen, Chunyi Wen, Xiaofeng Jia, Yu Li, Janet L Crane, Simon C Mears, Frederic B Askin, Frank J Frassica, Weizhong Chang, Jie Yao, John A Carrino, Andrew Cosgarea, Dmitri Artemov, Qianming Chen, Zhihe Zhao, Xuedong Zhou, Lee Riley, Paul Sponseller, Mei Wan, William Weijia Lu and Xu Cao doi:10.1038/nm.3143 Osteoarthritis has been believed to be caused by improper mechanical function of articular joints. Xu Cao and his colleagues now show that this mechanical process leads to upregulation of transforming growth factor β1 activity in mesenchymal stem cells of subchondral bone, resulting in aberrant bone formation, further destabilization of the joint and ultimately the onset of the disease. See also: News and Views by Bush & Beier Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection   pp713 - 721 John R Grainger, Elizabeth A Wohlfert, Ivan J Fuss, Nicolas Bouladoux, Michael H Askenase, Fanny Legrand, Lily Y Koo, Jason M Brenchley, Iain D C Fraser and Yasmine Belkaid doi:10.1038/nm.3189 Monocytes play an important part in the clearance of pathogens during infection. Yasmine Belkaid and her colleagues now report that inflammatory monocytes can also have a regulatory role. Specifically, these cells can mitigate the tissue damage induced by neutrophils during infection of mice with Toxoplasma gondii by releasing prostaglandin E2 in response to commensal bacteria. Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly   pp722 - 729 Qisheng Li, Veronique Pene, Siddharth Krishnamurthy, Helen Cha and T Jake Liang doi:10.1038/nm.3190 Lipid droplets have a key role in the assembly of hepatitis C virus (HCV) particles in liver cells. Jake Liang and colleagues now report that a host factor, IκB kinase-α is required for efficient production of HCV by increasing cellular lipid droplet content through its regulation of lipogenic genes in infected cells. The findings provide insight into some of the metabolic changes induced by HCV infection and may offer a new potential therapeutic target. See also: News and Views by Camus & Ott Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection   pp730 - 738 Pierre Guermonprez, Julie Helft, Carla Claser, Stephanie Deroubaix, Henry Karanje, Anna Gazumyan, Guillaume Darasse-Jeze, Stephanie B Telerman, Gaelle Breton, Heidi A Schreiber, Natalia Frias-Staheli, Eva Billerbeck, Marcus Dorner, Charles M Rice, Alexander Ploss, Florian Klein, Melissa Swiecki, Marco Colonna, Alice O Kamphorst, Matthew Meredith, Rachel Niec, Constantin Takacs, Fadi Mikhail, Aswin Hari, David Bosque, Tom Eisenreich, Miriam Merad, Yan Shi, Florent Ginhoux, Laurent Renia, Britta C Urban and Michel C Nussenzweig doi:10.1038/nm.3197 Pierre Guermonprez and colleagues have worked out how a subset of dendritic cells expands in individuals with severe malaria. Plasmodium infection causes an accumulation of xanthine in infected red blood cells. The researchers found that type I interferon triggers an increase in the enzyme that metabolizes xanthine to uric acid. Uric acid then acts on mast cells to release Flt3 ligand, an important regulator of dendritic cells, which in turn stimulate T cells to respond to the infection. See also: News and Views by Engwerda & Kumar Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells   pp739 - 746 Nicola Gagliani, Chiara F Magnani, Samuel Huber, Monica E Gianolini, Mauro Pala, Paula Licona-Limon, Binggege Guo, De'Broski R Herbert, Alessandro Bulfone, Filippo Trentini, Clelia Di Serio, Rosa Bacchetta, Marco Andreani, Leonie Brockmann, Silvia Gregori, Richard A Flavell and Maria-Grazia Roncarolo doi:10.1038/nm.3179 Type 1 regulatory (Tr1) T cells are characterized by their immunosuppressive activity and cytokine secretion profile; however, their isolation and enumeration are limited by the absence of specific markers. Here Richard Flavell, Maria-Grazia Roncarolo and colleagues report that CD49b and LAG-3 are coexpressed by human and mouse Tr1 cells. These markers can be used to isolate Tr1 cells in vitro and in vivo and can be used to quantify Tr1 cells in tolerant subjects. Letters Top Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells   pp747 - 752 Paul F Robbins, Yong-Chen Lu, Mona El-Gamil, Yong F Li, Colin Gross, Jared Gartner, Jimmy C Lin, Jamie K Teer, Paul Cliften, Eric Tycksen, Yardena Samuels and Steven A Rosenberg doi:10.1038/nm.3161 Identifying tumor-associated T cell epitopes can be laborious. Robbins et al. now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor regressions. The method will contribute to the identification of new tumor-specific epitopes that may further the development of effective T cell therapies for the treatment of patients with melanoma as well as a variety of additional malignancies. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I   pp753 - 759 Edward T Chouchani, Carmen Methner, Sergiy M Nadtochiy, Angela Logan, Victoria R Pell, Shujing Ding, Andrew M James, Helena M Cocheme, Johannes Reinhold, Kathryn S Lilley, Linda Partridge, Ian M Fearnley, Alan J Robinson, Richard C Hartley, Robin A J Smith, Thomas Krieg, Paul S Brookes and Michael P Murphy doi:10.1038/nm.3212 Nitric oxide donors protect from myocardial ischemia-reperfusion injury, but the underlying mechanisms have been unclear. Edward T Chouchani et al. uncover the molecular target of such donors, a cysteine residue in a subunit of complex I of the mitochondrial respiratory chain, and suggest that this cysteine residue has a general role in regulating complex I activity and modulating ischemia-reperfusion injury. See also: News and Views by Schumacker Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections   pp760 - 765 Karl Degenhardt, Manvendra K Singh, Haig Aghajanian, Daniele Massera, Qiaohong Wang, Jun Li, Li Li, Connie Choi, Amanda D Yzaguirre, Lauren J Francey, Emily Gallant, Ian D Krantz, Peter J Gruber and Jonathan A Epstein doi:10.1038/nm.3185 Abnormalities in how pulmonary veins connect to the heart underlie a type of congenital heart disease. Jonathan Epstein and his colleagues show that this condition, termed anomalous pulmonary venous connections, can be caused by mutation of the gene encoding the guidance protein semaphorin 3d and show how this protein acts in the embryo to pattern the developing pulmonary veins. Hypothalamic glucagon signaling inhibits hepatic glucose production   pp766 - 772 Patricia I Mighiu, Jessica T Y Yue, Beatrice M Filippi, Mona A Abraham, Madhu Chari, Carol K L Lam, Clair S Yang, Nikita R Christian, Maureen J Charron and Tony K T Lam doi:10.1038/nm.3115 Glucagon has traditionally been thought to act exclusively on the liver to promote endogenous glucose production in that organ. Tony Lam and his colleagues now show that it also acts on the hypothalamus to inhibit glucose production through a neural relay to the liver and that under high fat-fed conditions in rats this pathway is inhibited. This resistance may further explain the hyperglycemia that exists during obesity and diabetes. See also: News and Views by Edgerton & Cherrington Astrocyte-derived ATP modulates depressive-like behaviors   pp773 - 777 Xiong Cao, Liang-Ping Li, Qian Wang, Qiong Wu, Hong-Hai Hu, Meng Zhang, Ying-Ying Fang, Jie Zhang, Shu-Ji Li, Wen-Chao Xiong, Hua-Cheng Yan, Yu-Bo Gao, Ji-Hong Liu, Xiao-Wen Li, Li-Rong Sun, Yuan-Ning Zeng, Xin-Hong Zhu and Tian-Ming Gao doi:10.1038/nm.3162 Astrocytic dysfunction is a common feature in the brains of depressed subjects. Now, Xin-Hong Zhu and colleagues show that astrocytic release of ATP is reduced in the brains of stressed mice and that restoring brain ATP levels can rapidly reverse depressed behaviors in mice. Technical Reports Top Real-time in vivo analysis of T cell activation in the central nervous system using a genetically encoded calcium indicator   pp778 - 783 Marsilius Mues, Ingo Bartholomaus, Thomas Thestrup, Oliver Griesbeck, Hartmut Wekerle, Naoto Kawakami and Gurumoorthy Krishnamoorthy doi:10.1038/nm.3180 Marsilius Mues et al. have overcome previous obstacles precluding the expression of genetically encoded calcium indicators (GECIs) in immune cells by developing a new fluorescence resonance energy transfer-based GECI for the functional calcium imaging of T cells in vivo. Using two-photon imaging, the group traced the real-time activation of T cells in peripheral lymph nodes after antigen application, as well as in the CNS during experimental autoimmune encephalomyelitis. A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity   pp784 - 790 Dmitri Lodygin, Francesca Odoardi, Christian Schlager, Henrike Korner, Alexandra Kitz, Michail Nosov, Jens van den Brandt, Holger M Reichardt, Michael Haberl and Alexander Flugel doi:10.1038/nm.3182 The work of Dmitri Lodygin and his colleagues focuses on the important issue of when and where autoaggressive T cells are activated within their target organ to trigger autoimmune disease. Using intravital two-photon imaging and a new molecular sensor—a genetically encoded fluorescent sensor of nuclear factor of activated T cells (NFAT) combined with a fluorescently tagged version of nuclear histone protein H2B—the group was able to pinpoint key T cell activation events in experimental autoimmune encephalomyelitis, a model for multiple sclerosis. 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