Nature Medicine Contents: August 2013 Volume 19 Number 8 pp 947-1072

Advertisement Ozgene GM mouse services Vector Design * Vector Construction * Knockout Mice * Knockin Mice * Humanised Mice * Custom Breeding Let us know your gene of interest, desired modification and the scientific aim for your project. We will provide you with a Free Design. http://www.ozgene.com/gene-enquiry TABLE OF CONTENTS August 2013 Volume 19, Issue 8 Podcast Editorial News Correction Book Review News and Views Community Corner Between Bedside and Bench Research Highlights Review Perspective Articles Letter Technical Report Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Clinician Scientists Wanted in Singapore! Contact Singapore invites clinician-scientists to advance their career in Singapore. The top research and academic institutions in Singapore are recruiting clinician-scientists specialising in Cancer & Stem Cell Biology, Cardiovascular & Metabolic Disorders, Emerging Infectious Diseases, and more. Details of recruitment at http://www.contactsingapore.sg/Clinical/UK2013   Advertisement Nature Reprint Collection MicroRNAs from bench to clinic This Nature Reprint Collection presents some of the recent advances in moving microRNAs from basic research into the clinic both as diagnostic biomarkers and therapeutic targets.  Click here to access the Collection for free! Produced with support from:     Nature Medicine Podcast  Top Cardiac conundrum What the history of cardiac care can teach us about medical decision-making today, a new method for imaging tumors and a push to sequence 100,000 genomes with matched clinical data. Listen Now Editorial Top Adding fat to the fire   p947 doi:10.1038/nm.3301 The American Medical Association recently voted to recognize obesity as a disease. The potential implications of this resolution are manifold, but a better understanding of the underlying biology is necessary to help effect meaningful change. News Top Myriad sues developers of competing breast cancer tests   p948 Megan Scudellari doi:10.1038/nm0813-948 US National Cancer Institute's new Ras project targets an old foe   pp949 - 950 Helen Thompson doi:10.1038/nm0813-949 Uncommon ventures launch to tackle uncommon diseases   pp950 - 951 Elie Dolgin doi:10.1038/nm0813-950 Lack of small animal model hinders MERS coronavirus research   p952 Elizabeth Devitt doi:10.1038/nm0813-952 Trials challenging HIV drug doses could usher in huge cost cuts   p953 Monica Heger doi:10.1038/nm0813-953 Bacteria-killing dispute casts doubt on antibiotic development   p954 Brian Owens doi:10.1038/nm0813-954 Q&A Straight talk with...Sir John Chisholm   p955 doi:10.1038/nm0813-955 On 5 July, the UK government announced the launch of a new nonprofit company set up by the Department of Health called Genomics England, which aims to sequence 100,000 whole genomes, with linked clinical data, from people with cancer, rare diseases and infectious diseases[mdash]all by the end of 2017. Elie Dolgin spoke with Sir John Chisholm, the executive chair leading the effort. News in Brief Biomedical briefing   pp956 - 957 doi:10.1038/nm0813-956 See also: Editorial Correction Top Corrections   p957 doi:10.1038/nm0813-957 News Top News Feature A future, on ice   pp958 - 961 Alison McCook doi:10.1038/nm0813-958 An experimental approach promises to change the future for boys diagnosed today with cancer, allowing them to genetically father children of their own instead of facing a life of infertility. But will the science be ready when the children grow up, or are researchers subjecting families to another stressful decision for a hope that might not pan out? Alison McCook reports on the cutting-edge science[mdash]and controversy[mdash]surrounding the freezing of prepubescent tissue. Opinion A little better than placebo is still better than nothing   p962 Adrian S Dobs doi:10.1038/nm0813-962 Doctors often dismiss drugs as ineffective if they fail to outperform dummy pills in randomized trials. That's a mistake. When active medicines have few side effects and produce a strong placebo effect, such drugs, even if they prove just slightly better than placebo, should be embraced for the relief they can bring to patients who have few safe alternatives. Book Review Top The heroic era of cardiac care   p963 Goran K Hansson reviews Broken Hearts: The Tangled History of Cardiac Care by David S. Jones doi:10.1038/nm.3297 News and Views Top The origin of scar-forming kidney myofibroblasts   pp964 - 966 Allison A Eddy doi:10.1038/nm.3299 Whereas diabetes and hypertension predominate as the etiology of chronic kidney disease (CKD), all primary causes share a common progression pathway due to scarring or fibrosis. Understanding what cells are the sources of scar-forming cells is of utmost importance (pages 1047-1053). See also: Article by LeBleu et al. A step toward functionally characterized prostate cancer molecular subtypes   pp966 - 967 Francesca Demichelis and Gerhardt Attard doi:10.1038/nm.3285 ETS gene fusions and PTEN loss are common events in prostate cancer, but their interactions are not well understood. A new study in mice suggests that overexpression of ETS in the setting of PTEN loss increases androgen receptor binding and restores androgen receptor transcriptional activity (pages 1023-1029). See also: Article by Chen et al. LRH-1: orphaned, adopted and needed for pregnancy   pp968 - 969 Jan J Brosens, Andrew M Blanks and Emma S Lucas doi:10.1038/nm.3271 A new study shows that the orphan nuclear receptor liver receptor homolog 1 (LRH-1) wires the postovulatory rise in progesterone production to progesterone-dependent preparation of the endometrium for pregnancy, a process termed decidualization. Lack of Lrh-1 activity in either the ovary or uterus has catastrophic consequences for reproduction in mice (pages 1061-1066). See also: News and Views by Brosens et al. Obesity Notches up fatty liver   pp969 - 971 Michael P Czech doi:10.1038/nm.3293 Pathologic fatty liver paradoxically accompanies obesity and type 2 diabetes despite the crippling of insulin signaling, which is normally required for fat synthesis. The developmental signaling protein Notch is a hidden regulator of lipogenesis that amplifies signal transmissions to fat production in these metabolic diseases (pages 1054-1060). See also: Article by Pajvani et al. Huntington's disease: easing the NMDAR traffic jam   pp971 - 973 Anthony Daggett and X William Yang doi:10.1038/nm.3283 Excitatory neurotransmission through NMDA receptors (NMDARs) has a pivotal role in healthy brain function, and its dysfunction has long been implicated in the pathogenesis of neurodegenerative disorders, including Huntington's disease. A new study uncovers a molecular link between mutant huntingtin and aberrant trafficking of an unconventional NDMAR subunit (GluN3A). Targeting this disease mechanism in a Huntington's disease mouse model had multiple therapeutic benefits (pages 1030-1038). See also: Article by Marco et al. Nature Medicine JOBS of the week Postdoctoral Research Fellow Tulane University Health Sciences Center Postdoctoral Research Associate University of Oxford (Department of Biochemistry) PhD Position Heidelberg University, Institute of Physiology and Pathophysiology Biostatistician Medical Research Council More Science jobs from Nature Medicine EVENT Enhanced rare cell analysis � Visualize the invisible 30.10.13 Germany, Cologne More science events from Community Corner Top Modulating malaria with Wolbachia    pp974 - 975 doi:10.1038/nm.3298 Between Bedside and Bench Top Eosinophils in the Spotlight: Finding the link between obesity and asthma   pp976 - 977 Clare M Lloyd and Sejal Saglani doi:10.1038/nm.3296 How eosinophils function in different tissues during health and disease is not completely understood. On the one hand, they seem to be crucial in inflammatory disorders, which suggests that pathways related to their activation and regulation may be potential therapeutic targets. In asthma, the role of these cells is well known; however, airway inflammation owing to increased eosinophils in lung tissue in nonallergic asthma has only recently started to be in the limelight. In 'Bedside to Bench', Guy G. Brusselle, Tania Maes and Ken R. Bracke peruse the disease pathway triggering eosinophilic inflammation in nonallergic eosinophilic asthma and the potential targets that may lead to effective therapies. The authors also discuss a clinical study that highlights the need to phenotype patients using cellular and molecular markers to improve treatment responses. However, on the other hand, a recent study has also shown a homeostatic role of eosinophils in metabolism in fat tissue. In 'Bench to Bedside', Clare M. Lloyd and Sejal Saglani examine evidence that hints at the crucial role of the location of eosinophils in different tissues such as lung, where they cause inflammation, and visceral fat, where they improve glucose homeostasis. Clinical data that correlate lung tissue eosinophilia with obesity may spur new research to shed light on the role of these inflammatory cells in obese individuals with asthma and on how to improve treatments in these patients. Eosinophils in the Spotlight: Eosinophilic airway inflammation in nonallergic asthma   pp977 - 979 Guy G Brusselle, Tania Maes and Ken R Bracke doi:10.1038/nm.3300 Research Highlights Top Reproductive disorders: Probing preeclampsia | Diseases of the nervous system: Neurons on the move | Cancer: miR-22 attacks on several fronts | Cancer metabolism: Metabolic silencing | New from NPG | Neurodegeneration: Brain strains | Microbiome: Microbial mediators Review Top The role of autophagy in neurodegenerative disease   pp983 - 997 Ralph A Nixon doi:10.1038/nm.3232 This Review provides an overview of the role of autophagy, a key lysosomal degradative process, in neurodegenerative diseases. The study of various neurodegenerative diseases has shown that defects in autophagy can arise at different points in the pathway, and this has implications for the successful modulation of autophagy for therapeutic purposes. The Review also discusses the latest developments in targeting alterations in autophagy as a therapeutic strategy for neurodegenerative diseases. Perspective Top Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies   pp998 - 1004 Andrew S Lee, Chad Tang, Mahendra S Rao, Irving L Weissman and Joseph C Wu doi:10.1038/nm.3267 There is much interest in the applications of pluripotent stem cells for regenerative medicine. In this Perspective, the authors discuss the factors that might contribute to the potential risk of tumorigenicity from pluripotent stem cell therapies. They also outline recent developments in techniques that allow the sorting of tumorigenic species from nontumorigenic cells and offer a viewpoint into the future hurdles for moving pluripotent stem cell-based therapies from bench to bedside. Articles Top Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis   pp1005 - 1013 Mario Noti, Elia D Tait Wojno, Brian S Kim, Mark C Siracusa, Paul R Giacomin et al. doi:10.1038/nm.3281 Eosinophilic esophagitis (EoE) is characterized by esophageal eosinophilia, but the underlying mechanisms promoting eosinophil accumulation remain unclear. David Artis and his colleagues describe a new mouse model of EoE-like disease. The development of EoE-like disease is dependent on thymic stromal lymphopoietin (TSLP) and basophils, whereas inhibition of TSLP or depletion of basophils attenuates established disease. Moreover, individuals with EoE have increased TSLP expression and basophils in the esophagus, suggesting that the TSLP-basophil axis can be targeted in patients with EoE. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint   pp1014 - 1022 Srividya Swaminathan, Chuanxin Huang, Huimin Geng, Zhengshan Chen, Richard Harvey et al. doi:10.1038/nm.3247 During B cell development, cells that fail to productively rearrange their immunoglobulin VH-DJH gene segments to generate an in-frame junction that codes for a functional pre-B cell receptor are deleted. Markus Muschen and colleagues now report that Bach2 is a key component of this pre-B cell receptor checkpoint that enables the elimination of normal and transformed B cells with nonfunctional V(D)J rearrangements by regulating the expression of p53. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss   pp1023 - 1029 Yu Chen, Ping Chi, Shira Rockowitz, Phillip J Iaquinta, Tambudzai Shamu et al. doi:10.1038/nm.3216 Studies on a new conditional mouse model reveal that ETS transcription factors, which are often mutated in prostate cancer, cause transformation by altering the androgen-receptor cistrome, priming the prostate epithelium to respond to upstream signals such as PTEN loss. See also: News and Views by Demichelis & Attard Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models   pp1030 - 1038 Sonia Marco, Albert Giralt, Milos M Petrovic, Mahmoud A Pouladi, Rebeca Martinez-Turrillas et al. doi:10.1038/nm.3246 Huntington's disease is a neurodegenerative disorder associated with glutamate receptor dysfunction. Now Isabel Perez-Otano and colleagues report that the HTT protein that aggregates in the brains of individuals with the disease disrupts the ability of the adaptor protein PACSIN1 to keep the glutamate receptor subunit GluN3A away from the surface of neurons. See also: News and Views by Daggett & Yang Rev-erb-[alpha] modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy   pp1039 - 1046 Estelle Woldt, Yasmine Sebti, Laura A Solt, Christian Duhem, Steve Lancel et al. doi:10.1038/nm.3213 Bart Staels and his colleagues show that the transcription factor Rev-erb-[alpha] is highly expressed in oxidative muscle and, via loss- and gain-of-function experiments, including pharmacological activation, that it plays a key partin regulating the oxidative capacity of the muscle and exercise endurance. Origin and function of myofibroblasts in kidney fibrosis   pp1047 - 1053 Valerie S LeBleu, Gangadhar Taduri, Joyce O'Connell, Yingqi Teng, Vesselina G Cooke et al. doi:10.1038/nm.3218 Myofibroblasts are associated with organ fibrosis, but their origin and functional role remain unknown. Using multiple genetically engineered mice, the authors found that in the kidney, myofibroblasts arise from multiple sources[mdash]resident fibroblasts, bone marrow, endothelial cells and epithelial cells. Targeting these different populations may therefore be required to inhibit the accumulation of myofibroblasts in kidney fibrosis. See also: News and Views by Eddy Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability   pp1054 - 1060 Utpal B Pajvani, Li Qiang, Thaned Kangsamaksin, Jan Kitajewski, Henry N Ginsberg et al. doi:10.1038/nm.3259 Hepatic insulin resistance, a hallmark of type 2 diabetes, results in elevated blood sugar concentrations and fatty liver disease. Domenico Accili and his colleagues now show that inhibition of Notch signaling in the liver dampens the pathways leading to both conditions, thus improving these aspects of diabetes. See also: News and Views by Czech Letter Top Liver receptor homolog-1 is essential for pregnancy   pp1061 - 1066 Cong Zhang, Michael J Large, Raj Duggavathi, Francesco J DeMayo, John P Lydon et al. doi:10.1038/nm.3192 Liver receptor homolog-1 is an orphan nuclear receptor. Murphy and colleagues now show that this protein is crucial for different phases of pregnancy, including implantation and maintenance of the developing fetus, in mice, as well as for the proper function of human endometrial cells in culture. See also: News and Views by Brosens et al. Technical Report Top In vivo imaging of glucose uptake and metabolism in tumors   pp1067 - 1072 Simon Walker-Samuel, Rajiv Ramasawmy, Francisco Torrealdea, Marilena Rega, Vineeth Rajkumar et al. doi:10.1038/nm.3252 There is a pressing need for techniques that can be used for the noninvasive assessment of response to therapy and staging of disease. As many pathological conditions are associated with disordered glucose metabolism, such as diabetes, stroke and cancer, Simon Walker-Samuel and his colleagues have developed a noninvasive MRI-based method for imaging glucose uptake in vivo termed glucose chemical exchange saturation transfer (glucoCEST). This potentially cost-effective approach does not require the use of radiolabeled glucose analogs or ionizing radiation and allows nonlabeled glucose to be imaged at physiological quantities. Top Advertisement Nature Outlook Leukaemia While survival rates for some types of leukaemia have improved dramatically, this family of blood cancers remains a potentially fatal disease. Research in epigenetics, immunotherapy, and cell transplants offers hope.  Access the Outlook free online for six months. Produced with support from: Novartis Oncology, Baxter International, Onconova Therapeutics     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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