Nature Medicine Contents: August 2012 Volume 18 Number 8 pp 1155-1302

TABLE OF CONTENTS August 2012 Volume 18, Issue 8 Editorial News Book Review Correspondence News and Views Community Corner Between Bedside and Bench Research Highlights Review Brief Communication Articles Letters Technical Reports Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Nature.com presents Antibodypedia Finding the right antibody for the right application just got easier! Visit www.antibodypedia.com to find antibodies that have proved themselves effective for particular applications or to submit antibody validation data from your own experiments.   Advertisement Feel like your paper is lost in a sea of submissions? Scientific Reports publishes your research quickly and efficiently, and makes it freely available to the global scientific community. Learn more with our one minute illustrative video.   Editorial Top The fat of the matter   p1155 doi:10.1038/nm.2912 Amid an obesity epidemic, the approval of two new obesity drugs might revamp the clinical landscape of obesity treatment. News Top Point-of-care tests poised to alter course of HIV treatment   p1156 Lucas Laursen doi:10.1038/nm0812-1156 Race heats up for first-to-market drugs for resistant tuberculosis   p1157 Cassandra Willyard doi:10.1038/nm0812-1157 Potential first-in-class osteoporosis drug speeds through trials   p1158 Sarah C P Williams doi:10.1038/nm0812-1158 Overactive bladder, under scrutiny, gets a new treatment   p1159 Alisa Opar doi:10.1038/nm0812-1159a Study finds up to [dollar]5 billion in potential trial cost savings   p1159 Kathleen Raven doi:10.1038/nm0812-1159b New tracking system proposed to help recall faulty devices   p1160 Alla Katsnelson doi:10.1038/nm0812-1160 Clinical efficacy data on gene tests trails marketing in psychiatry   p1161 Elie Dolgin doi:10.1038/nm0812-1161 News in Brief Biomedical briefing   pp1162 - 1163 doi:10.1038/nm0812-1162 Q&A Straight talk with...Joe Selby   p1164 doi:10.1038/nm0812-1164 With a budget of $3.3 billion over the next seven years and an independent status, the Patient-Centered Outcomes Research Institute (PCORI) is tasked with creating the evidence base to help patients and doctors make more informed decisions about their medical choices. Elie Dolgin spoke with PCORI executive director Joe Selby, a family physician and clinical epidemiologist who joined the institute after 13 years as head of research at Kaiser Permanente, the California-based health provider. News Feature Nurses on trial   pp1165 - 1167 Rebecca Hersher doi:10.1038/nm0812-1165 When it comes to clinical trials, physicians almost always run the show. But a determined group of nurses is taking the reins, which some hope will lead to improved patient recruitment, particularly in women's health. Rebecca Hersher looks into whether the nurse is the principal investigator of the future. Opinion The time for pharmaceutical compulsory licensing has expired   p1168 Randall Kuhn and Reed F Beall doi:10.1038/nm0812-1168 The compulsory license mechanism is broken and will not bring drug access to the world's poorest nations. It's time to consider another option[mdash]a tax levied on patents[mdash]to fund drugs for developing countries, rather than the erratic compulsory licensing mechanism. Book Review Top Biotech's roots   p1169 Phillip A. Sharp reviews Genentech: The Beginnings of Biotech by Sally Smith Hughes doi:10.1038/nm.2888 Correspondence Top Cisplatin-induced primordial follicle oocyte killing and loss of fertility are not prevented by imatinib   pp1170 - 1172 Jeffrey B Kerr, Karla J Hutt, Michele Cook, Terence P Speed, Andreas Strasser, Jock K Findlay and Clare L Scott doi:10.1038/nm.2889 Reply to: Cisplatin-induced primordial follicle oocyte killing and loss of fertility are not prevented by imatinib   pp1172 - 1174 Emiliano Maiani, Claudia Di Bartolomeo, Francesca G Klinger, Stefano M Cannata, Sergio Bernardini, Sebastien Chateauvieux, Fabienne Mack, Maurizio Mattei, Massimo De Felici, Marc Diederich, Gianni Cesareni and Stefania Gonfloni doi:10.1038/nm.2852 News and Views Top TRP-ing up brain tumors   pp1175 - 1176 David L Schonberg, Shideng Bao and Jeremy N Rich doi:10.1038/nm.2894 Malignant gliomas are devastating, uniformly fatal cancers for which current therapies remain palliative. A new study in mice shows that neural precursor cells, abundant in neonatal brains, release a fatty acid factor that induces glioma cell death through the activation of TRPV1 channels, prolonging survival and potentially uncovering a new treatment strategy (pages 1232-1238). See also: Article by Stock et al. Nine lives for TH9s?   pp1177 - 1178 Weiping Zou and Nicholas P Restifo doi:10.1038/nm.2868 There is currently much interest in dissecting the mechanisms of tumor immunity. A new study shows that a subset of CD4+ T cells that produce the cytokine interleukin-9 (IL-9) mediate inhibition of melanoma growth in mice and that analogous IL-9-producing T cells are present in human skin (pages 1248-1253). Could such cells be manipulated to develop new therapeutic strategies for melanoma? See also: Article by Purwar et al. The elusive source of myofibroblasts: problem solved?   pp1178 - 1180 Jeremy S Duffield doi:10.1038/nm.2867 Fibrosis is omnipresent and contributes to a substantial proportion of all natural deaths. A recent study (pages 1262-1270) provides evidence that the mysterious perivascular cell, also known as the pericyte, is the cell type responsible for fibrotic disease in skin and skeletal muscle. See also: Article by Dulauroy et al. Febrile seizures and the wandering granule cell   pp1180 - 1182 Rod C Scott and Gregory L Holmes doi:10.1038/nm.2898 Prolonged febrile seizures in young children have long been suspected to lead to temporal lobe epilepsy, but how this occurs has been unclear. A new study (pages 1271-1278) in rats showing that febrile seizures induce aberrant migration of cells in the temporal lobe suggests this may be a crucial component in the development of epilepsy. See also: Article by Koyama et al. Fetuin-A: the missing link in lipid-induced inflammation   pp1182 - 1183 Jan Heinrichsdorff and Jerrold M Olefsky doi:10.1038/nm.2869 The liver secretory protein fetuin-A (FetA) is now shown to act as an adaptor protein between free fatty acids (FFAs) and Toll-like receptor 4 (TLR4), providing the missing link between FFAs and chronic low-grade inflammation that impairs insulin sensitivity (pages 1279-1285). See also: Letter by Pal et al. The dark side of the oxidative force in angiogenesis   pp1184 - 1185 Bethany A Kerr and Tatiana V Byzova doi:10.1038/nm.2881 A new mechanism regulating pathological angiogenesis has been identified that involves the activation of ataxia-telangiectasia mutated (Atm) kinase in response to reactive oxygen species. Importantly, this Atm-dependent pathway is specifically activated in pathological, but not in normal, angiogenesis, suggesting that it could be therapeutically targeted in diseases associated with pathological angiogenesis (pages 1208-1216). See also: Article by Okuno et al. Nature Medicine JOBS of the week Assistant Professor- Pharmacology Purdue University Research Assistant - ES Cell Culture / Microinjection Medical Research Council, Mary Lyon Centre Research Assistant / Associate in Theoretical and Computational Nanobiomaterials Imperial College London Lecturer in Plant Biology University of York PhD Studentship in Computational and Systems Biology : Dublin, Ireland Teagasc & Systems Biology Ireland Researcher for HIV molecular and immunology studies Virus Research and Development (VIRD) Laboratory, Department of Microbiology Diagnostic and Virology, Sector for Diagnostic and Infectious Control, Statens Serum Institut, Denmark PhD Studentship University College London Postdoctoral fellowship in human cytotoxic lymphocyte immunobiology Baylor College of Medicine (BCM)/ Texas Children's Hospital (TCH) Postdoc postion in molecular biology at UCLA UCLA PhD Studentship - Quadruple Media Depth Filtration for Water Purification Cranfield University More Science jobs from Nature Medicine EVENT The 15th European Microscopy Congress 16.-21.09.12 Manchester, UK More science events from Community Corner Top Milk modulates the microbiota   pp1186 - 1187 doi:10.1038/nm.2902 Between Bedside and Bench Top A complex microworld in the gut: Gut microbiota and cardiovascular disease connectivity   pp1188 - 1189 Michael R Howitt and Wendy S Garrett doi:10.1038/nm.2895 Millions of healthy bacteria colonize our guts from the moment we are born. Changes in the composition and abundance of these commensals affect the entire immune system and can predispose us to a variety of diseases, including intestinal infections, inflammatory and metabolic diseases, and cancer. The gut microbiome interacts not only with the host mucosa but also with potential pathogens; understanding what interactions and pathways are crucial for maintaining homeostasis and protecting the host from harmful bacteria and diseases can open new avenues to developing gut microbiota-based therapeutic approaches. In 'Bench to Bedside', Michael R. Howitt and Wendy S. Garrett examine the importance of metabolic crosstalk between the microbiota and the host in human metabolism and the development of cardiovascular disease. This adds one more layer of complexity to understanding what contributes to this pathology and how to harness the microbiota and their metabolic pathways to prevent it. In 'Bedside to Bench', Nobuhiko Kamada, Grace Chen and Gabriel Nunez discuss how targeting interactions between commensals and bacteria causing intestinal disease can lead to effective therapies to control these infections, which currently seem to lack an adequate treatment. Unraveling how commensals help the host prevent or block colonization of these pathogens can suggest new ways to increase our armamentarium to deal with these sometimes deadly intestinal infections. A complex microworld in the gut: Harnessing pathogen-commensal relations   pp1190 - 1191 Nobuhiko Kamada, Grace Chen and Gabriel Nunez doi:10.1038/nm.2900 Research Highlights Top Neuroscience: Restricted astrocytes | Reproductive biology: Bringing up baby | Cancer: Stromal protection from therapy | Virology: 'Influenzing' the host response | Neuroloscience: It's all in the details | Immunity: Gut bugs alter antiviral immunity | Cardiovascular diseases: STAMPing down inflammation | New from NPG Review Top Epigenetic mechanisms in neurological disease   pp1194 - 1204 Mira Jakovcevski and Schahram Akbarian doi:10.1038/nm.2828 This review describes how the evolving field of neuroepigenetics can provide a new understanding of the mechanisms involved in neurodevelopmental and neurodegenerative disorders. It also discusses how epigenetic therapeutics that have been approved for other diseases, such as cancer, could be useful in modulating neurological conditions associated with epigenetic abnormalities. Brief Communication Top Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers   pp1205 - 1207 Berengere Fromy, Eric Lingueglia, Dominique Sigaudo-Roussel, Jean Louis Saumet and Michel Lazdunski doi:10.1038/nm.2844 A slight mechanical pressure applied to healthy skin results in blood vessel dilation, preserving blood flow. Defects in this vasodilatory response lead to an increased risk of pressure ulcers. Fromy et al. identify the neuronal mechanosensor that mediates this response in both rodents and humans: the ion channel Asic3. Articles Top Pathological neoangiogenesis depends on oxidative stress regulation by ATM   pp1208 - 1216 Yuji Okuno, Ayako Nakamura-Ishizu, Kinya Otsu, Toshio Suda and Yoshiaki Kubota doi:10.1038/nm.2846 Yuji Okuno et al. find that pathological angiogenesis in mice requires dampening of oxidative stress. In the absence of the ATM protein kinase, increased oxidative stress leads to activation of the p38[alpha] protein kinase and inhibition of new blood vessel growth. These findings run counter to the commonly held concept that decreasing oxidative stress would inhibit pathological angiogenesis and suggest new targets for treating diseases involving abnormal blood vessel growth. See also: News and Views by Kerr & Byzova The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis   pp1217 - 1223 Eric P Schmidt, Yimu Yang, William J Janssen, Aneta Gandjeva, Mario J Perez, Lea Barthel, Rachel L Zemans, Joel C Bowman, Dan E Koyanagi, Zulma X Yunt, Lynelle P Smith, Sara S Cheng, Katherine H Overdier, Kathy R Thompson, Mark W Geraci, Ivor S Douglas, David B Pearse and Rubin M Tuder doi:10.1038/nm.2843 The glycocalyx is a layer of proteoglycans and complex carbohydrates that lines the endothelial cell surface in blood vessels. Schmidt et al. show that in mouse models of sepsis, lung inflammation and injury depend on glycocalyx degradation, which increases neutrophil access to endothelial adhesion molecules. The authors also provide data indicating the potential relevance of this mechanism of lung injury to humans with sepsis. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape   pp1224 - 1231 Bradley N Bidwell, Clare Y Slaney, Nimali P Withana, Sam Forster, Yuan Cao, Sherene Loi, Daniel Andrews, Thomas Mikeska, Niamh E Mangan, Shamith A Samarajiwa, Nicole A de Weerd, Jodee Gould, Pedram Argani, Andreas Moller, Mark J Smyth, Robin L Anderson, Paul J Hertzog and Belinda S Parker doi:10.1038/nm.2830 The authors identify Irf7 and associated interferon signaling as an important factor suppressing bone metastasis of breast cancers. Irf7 is lost in experimental metastasis and human bone metastastic tissue, and this fosters an immunosuppressive environment that facilitates metastasis. Manipulating this innate immune signaling pathway emerging from tumor cells by interferon administration had beneficial effects in mouse models by reducing bone metastasis and increasing survival time. Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1   pp1232 - 1238 Kristin Stock, Jitender Kumar, Michael Synowitz, Stefania Petrosino, Roberta Imperatore, Ewan St J Smith, Peter Wend, Bettina Purfurst, Ulrike A Nuber, Ulf Gurok, Vitali Matyash, Joo-Hee Walzlein, Sridhar R Chirasani, Gunnar Dittmar, Benjamin F Cravatt, Stefan Momma, Gary R Lewin, Alessia Ligresti, Luciano De Petrocellis, Luigia Cristino, Vincenzo Di Marzo, Helmut Kettenmann and Rainer Glass doi:10.1038/nm.2827 The authors uncover a mechanism for the known antitumor effect exerted by neural precursor cells (NPCs). NPCs migrate into tumors in vivo and secrete endovanilloids, which act as agonists for TRPV1, their receptor expressed by glioma cells. TRPV1 activation causes ER stress and glioma cell death. The reported elevated concentration of TRPV1 in human gliomas and the antitumor effect of synthetic vanilloids suggest that this pathway could be a point of therapeutic intervention and that differential NPC activity, such as that modulated by age, could be a factor influencing brain tumorigenesis. See also: News and Views by Schonberg et al. MDM4 is a key therapeutic target in cutaneous melanoma   pp1239 - 1247 Agnieszka Gembarska, Flavie Luciani, Clare Fedele, Elisabeth A Russell, Michael Dewaele, Stephanie Villar, Aleksandra Zwolinska, Sue Haupt, Job de Lange, Dana Yip, James Goydos, Jody J Haigh, Ygal Haupt, Lionel Larue, Aart Jochemsen, Hubing Shi, Gatien Moriceau, Roger S Lo, Ghanem Ghanem, Mark Shackleton, Federico Bernal and Jean-Christophe Marine doi:10.1038/nm.2863 Although loss-of-function p53 alterations are widespread in many tumors, melanomas typically do not harbor TP53 mutations. This report uncovers upregulation of MDM4 as a frequent trait of melanomas that contributes to tumorigenesis by inactivating p53 signaling. MDM4 is required for growth and survival of melanoma cell lines, and compounds that can target MDM4 are effective against melanoma in vivo and against tumors resistant to BRAF-targeted therapy in vitro. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells   pp1248 - 1253 Rahul Purwar, Christoph Schlapbach, Sheng Xiao, Hong Soon Kang, Wassim Elyaman, Xiaodong Jiang, Anton M Jetten, Samia J Khoury, Robert C Fuhlbrigge, Vijay K Kuchroo, Rachael A Clark and Thomas S Kupper doi:10.1038/nm.2856 In this issue, Thomas Kupper and colleagues report that mice deficient for ROR-[gamma] or interleukin-23 (IL-23) receptor showed impaired melanoma growth. Tumor growth inhibition was dependent in part on IL-9 and T helper type 9 (TH9) cells. Moreover, the authors showed that IL-9 acts on mast cells rather than T or B cells to mediate its antitumor effects and that TH9 cells are present in human blood and skin, suggesting that a role for TH9 cells in human tumor immunity should be explored. See also: News and Views by Zou & Restifo Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival   pp1254 - 1261 Steffen Walter, Toni Weinschenk, Arnulf Stenzl, Romuald Zdrojowy, Anna Pluzanska, Cezary Szczylik, Michael Staehler, Wolfram Brugger, Pierre-Yves Dietrich, Regina Mendrzyk, Norbert Hilf, Oliver Schoor, Jens Fritsche, Andrea Mahr, Dominik Maurer, Verona Vass, Claudia Trautwein, Peter Lewandrowski, Christian Flohr, Heike Pohla, Janusz J Stanczak, Vincenzo Bronte, Susanna Mandruzzato, Tilo Biedermann, Graham Pawelec, Evelyna Derhovanessian, Hisakazu Yamagishi, Tsuneharu Miki, Fumiya Hongo, Natsuki Takaha, Kosei Hirakawa, Hiroaki Tanaka, Stefan Stevanovic, Jurgen Frisch, Andrea Mayer-Mokler, Alexandra Kirner, Hans-Georg Rammensee, Carsten Reinhardt and Harpreet Singh-Jasuja doi:10.1038/nm.2883 In this issue, Walter et al. report the results of two clinical trials of a new therapeutic vaccine, IMA901, for the treatment of renal cell carcinoma (RCC). IMA901 consists of ten tumor-associated peptides identified as naturally presented T cell epitopes in RCC, and the authors show longer overall survival in subjects with immune responses to multiple vaccine peptides and identify serum and cellular biomarkers that may help predict overall survival in future studies of the vaccine. Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury   pp1262 - 1270 Sophie Dulauroy, Selene E Di Carlo, Francina Langa, Gerard Eberl and Lucie Peduto doi:10.1038/nm.2848 Organ fibrosis often leads to end-stage organ failure, but the origin of key profibrotic cell types is still unclear. Lucie Peduto and her colleagues have used genetic lineage tracing and pharmacological ablation techniques to show that ADAM12+ perivascular cells are a key source of profibrotic cells in acute skin and muscle injury in the mouse. They also show that knockdown of ADAM12 expression is beneficial, suggesting a possible therapeutic target for the treatment of fibrosis. See also: News and Views by Duffield GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy   pp1271 - 1278 Ryuta Koyama, Kentaro Tao, Takuya Sasaki, Junya Ichikawa, Daisuke Miyamoto, Rieko Muramatsu, Norio Matsuki and Yuji Ikegaya doi:10.1038/nm.2850 Febrile seizures during childhood are linked to the development of chronic epilepsy. Now, Ryuta Koyama and colleagues show that febrile seizures are associated with enhanced GABAergic excitation and ectopic granule cell migration in the hippocampus. See also: News and Views by Scott & Holmes Letters Top Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance   pp1279 - 1285 Durba Pal, Suman Dasgupta, Rakesh Kundu, Sudipta Maitra, Gobardhan Das, Satinath Mukhopadhyay, Sukanta Ray, Subeer S Majumdar and Samir Bhattacharya doi:10.1038/nm.2851 Excess free fatty acids (FFAs) are known to induce insulin resistance, and a role for TLR4 has been implicated in this process. But FFAs are believed to be incapable of binding TLR4 directly. In a new study, Samir Bhattacharya and colleagues show that fetuin-A acts as an intermediary in this process by bindings FFAs and presenting them to TLR4. These results suggest fetuin-A as a new target to treat insulin resistance and diabetes. See also: News and Views by Heinrichsdorff & Olefsky Ultraviolet radiation damages self noncoding RNA and is detected by TLR3   pp1286 - 1290 Jamie J Bernard, Christopher Cowing-Zitron, Teruaki Nakatsuji, Beda Muehleisen, Jun Muto, Andrew W Borkowski, Laisel Martinez, Eric L Greidinger, Benjamin D Yu and Richard L. Gallo doi:10.1038/nm.2861 Ultraviolet radiation induces an inflammatory response in the skin, but it remains unclear how cells in the skin detect this damage and trigger an inflammatory response. Richard L. Gallo and his colleagues report that ultraviolet radiation damages self noncoding RNA. These modified RNA are released from irradiated keratinocytes and act as a danger signal that is detected by Toll-like receptor 3 (TLR3), which is required for the induction of proinflammatory cytokine release and for radiation-induced immune suppression. Technical Reports Top Large intestine-targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection   pp1291 - 1296 Qing Zhu, James Talton, Guofeng Zhang, Tshaka Cunningham, Zijian Wang, Robert C Waters, James Kirk, Barbel Eppler, Dennis M Klinman, Yongjun Sui, Susan Gagnon, Igor M Belyakov, Russell J Mumper and Jay A Berzofsky doi:10.1038/nm.2866 The mucosa of the large intestine mucosa is an effective vaccination site for induction of protective mucosal immunity against rectal or vaginal viral infection but clinically is impractical. Here Qing Zhu et al. have developed an oral delivery system that encapsulates vaccine into pH-dependent poly(DL-lactic-co-glycolic acid) (PLGA) nanoparticles coated with Eudragit to protect against the low pH and enzymatic destruction of the stomach. This approach was shown to selectively target the large intestine in mice and induce antigen-specific T and B cell responses similar to that observed with intracolorectal vaccination. Simultaneous functional photoacoustic and ultrasonic endoscopy of internal organs in vivo    pp1297 - 1302 Joon-Mo Yang, Christopher Favazza, Ruimin Chen, Junjie Yao, Xin Cai, Konstantin Maslov, Qifa Zhou, K Kirk Shung and Lihong V Wang doi:10.1038/nm.2823 Joon-Mo Yang and colleagues have developed a new endoscopic technique for the in vivo imaging of internal organs, combining endoscopic ultrasound and photoacoustic endoscopy in a single instrument. In addition to improved resolution, imaging depth, multimodal contrast, and distal-end scanning, the new hybrid imaging modality can also provide functional information such as hemoglobin concentration and blood oxygenation. Feasibility is shown in vivo by simultaneous photoacoustic endoscopy and endoscopic ultrasound imaging of the upper and lower gastrointestinal tracts of rats and rabbits. 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. You can change or discontinue your e-mail alerts at any time, by modifying your preferences on your nature.com account at: www.nature.com/myaccount (You will need to log in to be recognised as a nature.com registrant) For further technical assistance, please contact our registration department For print subscription enquiries, please contact our subscription department For other enquiries, please contact our customer feedback department Nature Publishing Group | 75 Varick Street, 9th Floor | New York | NY 10013-1917 | USA Nature Publishing Group's worldwide offices: London - Paris - Munich - New Delhi - Tokyo - Melbourne San Diego - San Francisco - Washington - New York - Boston Macmillan Publishers Limited is a company incorporated in England and Wales under company number 785998 and whose registered office is located at Brunel Road, Houndmills, Basingstoke, Hampshire RG21 6XS. © 2012 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.