Nature Medicine Contents: April 2014 Volume 20 Number 4 pp 319-449

If you are unable to see the message below, click here to view.

Advertisement New from Exiqon Services: microRNA and small RNA NGS - A complete sample-to-answer solution - Comprehensive analysis including biological interpretation - Experiments set up in close cooperation with our microRNA and NGS experts Learn more  TABLE OF CONTENTS April 2014 Volume 20, Issue 4 Podcast Editorial News Book Review News and Views Community Corner Between Bedside and Bench Articles Letters Technical Reports Research Highlights Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Nature Outlook Vaccines Waging a global battle to prevent disease  Access the Outlook free online for six months. Produced with support from the New Venture Fund, United Nations Children's Fund (UNICEF), and GAVI Alliance, with additional support from the Bill & Melinda Gates Foundation.    Nature Medicine Podcast  Top Control issues Why drug therapy might be helpful for HIV controllers and a new blood test that can diagnose Alzheimer's disease years before symptoms arise. Listen Now Editorial Top The price of good health   p319 doi:10.1038/nm.3538 News Top Report urges controversial 'delinkage' to foster new antibiotics   p320 David Holmes doi:10.1038/nm0414-320 Adaptive methods help drug sponsors find best treatment dose   p321 Elie Dolgin doi:10.1038/nm0414-321 To foster screening, new colon cancer tests emphasize convenience   pp322 - 323 Cassandra Willyard doi:10.1038/nm0414-322 Long-acting HIV drugs advanced to overcome adherence challenge   pp323 - 324 Elie Dolgin doi:10.1038/nm0414-323 Q&A Straight talk with...Victor Dzau   p325 doi:10.1038/nm0414-325 In July, Victor Dzau will start his six-year term as president of the US Institute of Medicine (IOM). A cardiologist and researcher by training, Dzau currently serves as chancellor for health affairs at Duke University in Durham, North Carolina. Roxanne Khamsi spoke with Dzau about his vision for the IOM. News in Brief Biomedical briefing   pp326 - 327 doi:10.1038/nm0414-326 Corrections   p327 doi:10.1038/nm0414-327 News Feature Control issues   pp328 - 330 Alla Katsnelson doi:10.1038/nm0414-328 People infected with HIV who control the infection without antiretroviral drug therapy have often served as foot soldiers for science, but now science owes them some answers. If the rare good fortune of being a so-called 'HIV controller' comes with a price—namely, immune activation that raises a person's risks of developing cardiovascular disease, diabetes and other health problems—might antiretroviral medications give these patients' overactive immune systems a much-needed break? Alla Katsnelson investigates. Book Review Top A medical alternative   p331 Rama Amara reviews Do You Believe in Magic? The Sense and Nonsense of Alternative Medicine by Paul A. Offit doi:10.1038/nm.3515 News and Views Top ECM stiffness paves the way for tumor cells   pp332 - 333 Victoria Seewaldt doi:10.1038/nm.3523 In the mammary gland, the stiffness of extracellular matrix (ECM) collagen is thought to influence tumor progression and clinical outcome. A new mechanism orchestrated by a microRNA circuit is shown to mediate the physical effects of the microenvironment on tumor cell progression. The findings may explain how increased breast matrix stiffness is associated with poor survival and could help identify women with aggressive breast cancer (pages 360-367). See also: Article by Mouw et al. Targeting a new regulator of erythropoiesis to alleviate anemia   pp334 - 335 Robert F Paulson doi:10.1038/nm.3524 Anemia is a debilitating condition that can be complicated by ineffective erythropoiesis. Two new studies identify GDF11 as a regulator of erythropoiesis and show that its inhibition in mouse models of anemia with ineffective erythropoiesis restores normal erythropoietic differentiation and alleviates anemia (pages 398-407 and 408-414). See also: Article by Dussiot et al. | Letter by Suragani et al. Hypoferremia of infection: a double-edged sword?   pp335 - 337 Kristen L Lokken, Renee M Tsolis and Andreas J Baumler doi:10.1038/nm.3526 Pharmacologic modulation of iron metabolism may be a potential strategy to control infection caused by the intracellular bacteria Salmonella enterica var. Typhimurium (S. typhimurium) (pages 419-424). The molecular mechanism involves the estrogen-related receptor γ (ERRγ) in the liver, which can be targeted with an inverse agonist to improve survival of infected animals. See also: Letter by Kim et al. FXR: the key to benefits in bariatric surgery?   pp337 - 338 Folkert Kuipers and Albert K. Groen doi:10.1038/nm.3525 Bariatric surgery reduces the weight of morbidly obese individuals and exerts beneficial effects on associated metabolic disorders such as type 2 diabetes. However, despite growing traction in this area of metabolic research, questions remain as to the mechanisms that lead to these benefits. New findings propose that the bile acid-activated nuclear receptor FXR mediates the metabolic improvement seen after one particular bariatric surgery approach and that this may involve alterations in the microbiome. Nature Medicine JOBS of the week Postdoctoral Research Fellow in Theoretical Material Physics - Thermoelectric Materials University of Oslo PhD studentship on flexible atomically-thin materials for optoelectronics University of Exeter An Engineer for thin film nano-materials (m / f) Centre de Recherche Public - Gabriel Lippmann Binary Polyoxometalates / Magnetic NanoCrystals materials Pierre et Marie Curie University- Paris VI, Paris, France Postdoc in Biophysics / Biomaterials Indiana University - Bloomington More Science jobs from Nature Medicine EVENT Pharmacology 2014 16.12.14 London, UK More science events from Community Corner Top Cancer therapy resistance: chasing epigenetics   pp340 - 341 doi:10.1038/nm.3528 Between Bedside and Bench Top Tumor Heterogeneity Confounds and Illuminates: Assessing the implications   pp342 - 344 Maria Kleppe and Ross L Levine doi:10.1038/nm.3522 Certain biological features are inherent traits of cancer, yet some of them still hold mysteries for researchers and clinicians. The heterogeneity of a tumor mass is an old concept that has lately become both a puzzling factor and a feature that should be harnessed to better understand tumor vulnerabilities. Improved scientific approaches to further determine and uncover the meaning of these heterogeneous features are still needed to translate findings into ways to develop therapies, identify drug response biomarkers and stratify patients. In Bedside to Bench, Maria Kleppe and Ross L. Levine look at recent clinical cancer trials that have advanced the field and discuss main questions regarding the role of tumor heterogeneity in predicting therapeutic response and tumor progression. In addition, they raise awareness of the relevance of the interactions among different tumor entities and their contribution to the malignancy of the whole tumor. In Bench to Bedside, Kornelia Polyak peruses studies that uncover specific mutations conferring endocrine drug resistance in breast tumors and that add to our knowledge of the evolution and architecture of tumors, and she discusses how this can be used to implement drug regimens. Tumor Heterogeneity Confounds and Illuminates: A case for Darwinian tumor evolution   pp344 - 346 Kornelia Polyak doi:10.1038/nm.3518 Research Highlights Top Immunology: ILCs in the margins | Adult neurogenesis: Making new neurons | Metastases: Lighting the way to melanoma metastasis | Microbiota: Dysbiosis as a diagnostic | Medical genetics: Narrowing down obesity genes | HIV infections: Editing the way to therapy for HIV | Amyotrophic lateral sclerosis: Mayhem-making microglia | Nutrition: Dietary protein and lifespan Articles Top Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation   pp350 - 359 Emanuel Rognoni, Moritz Widmaier, Madis Jakobson, Raphael Ruppert, Siegfried Ussar et al. doi:10.1038/nm.3490 Mutations in Kindlin-1 result in Kindler syndrome, which is marked by skin blistering, premature skin aging and increased risk for skin cancer. Reinhard Fassler and his colleagues have developed a new mouse model of the condition, revealing new cellular and molecular mechanistic insight into the pathology of the syndrome. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression   pp360 - 367 Janna K Mouw, Yoshihiro Yui, Laura Damiano, Russell O Bainer, Johnathon N Lakins et al. doi:10.1038/nm.3497 Mouw et al. delineate a molecular pathway by which matrix stiffness promotes tumor malignancy. Upon matrix stiffening, integrin signaling is engaged, triggering a signaling cascade that regulates the protumorigenic microRNA miR-18a. This leads to downregulation of PTEN and activation of oncogenic signaling. The pathway provides a link between mechanotransduction, miR regulation and oncogene activation that integrates biophysical changes into tumor progression and can also be altered in human tumors. See also: News and Views by Seewaldt MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1   pp368 - 376 Andreas Schober, Maliheh Nazari-Jahantigh, Yuanyuan Wei, Kiril Bidzhekov, Felix Gremse et al. doi:10.1038/nm.3487 Atherosclerotic lesions develop preferentially at sites of disturbed blood flow. As shown by Christian Weber and his coworkers, this predilection stems from effects of disturbed blood flow on endothelial expression of the microRNA miR-126-5p, which maintains the proliferative reserve of endothelial cells through repression of the Notch pathway inhibitor Dlk1. Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity   pp377 - 384 Bhama Ramkhelawon, Elizabeth J Hennessy, Mickael Menager, Tathagat Dutta Ray, Frederick J Sheedy et al. doi:10.1038/nm.3467 Obesity is marked by a state of low-grade inflammation, including the accumulation of macrophages in the adipose tissue, which results in insulin resistance. Kathryn Moore and her colleagues now show that the neuronal guidance molecule, netrin-1, is upregulated in fat cells during obesity and leads to the retention of macrophages in this tissue. They also show that its genetic deletion in mice prevents the development of insulin resistance by a high-fat diet. MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes   pp385 - 397 Amin Ardestani, Federico Paroni, Zahra Azizi, Supreet Kaur, Vrushali Khobragade et al. doi:10.1038/nm.3482 Type 1 diabetes (T1D) and type 2 diabetes (T2D) are both hallmarked by loss of insulin-producing pancreatic beta cells. Kathrin Maedler and her colleagues now show that the kinase MST1 is upregulated by diabetic conditions in beta cells, resulting in their dysfunction and their apoptosis. They also show that genetic knockout of the gene encoding Mst1 results in protection from diabetes in T1D and T2D mouse models. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia   pp398 - 407 Michael Dussiot, Thiago T Maciel, Aurelie Fricot, Celine Chartier, Olivier Negre et al. doi:10.1038/nm.3468 Michael Dussiot et al. show that an activin receptor IIA ligand trap ameliorates anemia in a mouse model of β-thalassemia by blocking the deleterious effects of GDF11. Mechanistically, GDF11 inactivation reversed ineffective erythropoiesis by promoting terminal erythroblast differentiation and by inducing apoptosis of immature erythroblasts. Also in this issue, Rajasekhar Suragani et al. show related findings using a modified activin receptor IIB ligand trap. See also: News and Views by Paulson | Letter by Suragani et al. Letters Top Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis   pp408 - 414 Rajasekhar N V S Suragani, Samuel M Cadena, Sharon M Cawley, Dianne Sako, Dianne Mitchell et al. doi:10.1038/nm.3512 Rajasekhar Suragani et al. show that a modified activin receptor IIB ligand trap increases red blood cell numbers in mice, rats and monkeys and ameliorates anemia in mice and rats, including in a mouse model of myelodysplastic syndromes. The ligand trap binds to the cytokine GDF11 and acts by inhibiting Smad2/3 signaling, thereby reversing ineffective erythropoiesis. Also in this issue, Michael Dussiot et al. show related findings using a wild-type activin receptor IIA ligand trap. See also: News and Views by Paulson | Article by Dussiot et al. Plasma phospholipids identify antecedent memory impairment in older adults   pp415 - 418 Mark Mapstone, Amrita K Cheema, Massimo S Fiandaca, Xiaogang Zhong, Timothy R Mhyre et al. doi:10.1038/nm.3466 Howard Federoff and colleagues have identified a ten-metabolite profile in the blood that can determine with 90% certainty whether a cognitively normal elderly person will go on to develop dementia symptoms in the next 2-3 years. The findings could help with patient selection for clinical trials aimed at preventing dementia. Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis   pp419 - 424 Don-Kyu Kim, Jae-Ho Jeong, Ji-Min Lee, Kwang Soo Kim, Seung-Hwan Park et al. doi:10.1038/nm.3483 Mammals respond to bacterial infection by inducing the expression of hepcidin, which restricts serum iron levels through its effects on macrophage iron export and thereby limits systemic bacterial growth. Kim et al. now report that the macrophage-tropic pathogen Salmonella typhimurium exploits this pathway by triggering the expression of estrogen-related receptor-γ (ERR-γ), which they show increases hepcidin expression and enhances S. typhimurium growth. See also: News and Views by Lokken et al. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo    pp425 - 429 C Korin Bullen, Gregory M Laird, Christine M Durand, Janet D Siliciano and Robert F Siliciano doi:10.1038/nm.3489 Latency-reversing agents (LRAs) have been tested in HIV-1-infected individuals in the hopes of activating the latent viral reservoir and contributing to efforts to eradicate the virus. Robert F. Siliciano and his colleagues now report that most individual LRAs fail to reactivate latent virus in cells from infected individuals and that in vitro models of latency do not adequately reflect the ability of these agents to induce latent virus ex vivo. Technical Reports Top Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA   pp430 - 435 Alain R Thierry, Florent Mouliere, Safia El Messaoudi, Caroline Mollevi, Evelyne Lopez-Crapez et al. doi:10.1038/nm.3511 Alain Thierry and his colleagues offer a new allele-specific, quantitative PCR-based method designed for the detection of point mutations and determination of mutation load using circulating cell-free DNA isolated from blood. In a blinded study of patients with colorectal cancer, the method exhibited 98% specificity and 92% sensitivity for the seven KRAS point mutations tested and compared favorably with other routinely used detection methods. The approach should help in patients selection for anti-EGFR treatments and for monitoring resistance. Multiplexed ion beam imaging of human breast tumors   pp436 - 442 Michael Angelo, Sean C Bendall, Rachel Finck, Matthew B Hale, Chuck Hitzman et al. doi:10.1038/nm.3488 The work of Michael Angelo and colleagues uses multiplexed ion beam imaging (MIBI) to localize and visualize protein expression in a manner analogous to immunohistochemistry (IHC) while circumventing some of the limitations of conventional IHC with clinical samples. MIBI uses secondary ion mass spectrometry to image antibodies tagged with isotopically pure elemental metal reporters, expanding the number of targets that can be analyzed simultaneously to about 100. The approach, used here to image breast tumor tissue sections, offers over a five-log dynamic range and compatibility with standard formalin-fixed, paraffin-embedded tissue sections. Label-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectance microscopy   pp443 - 449 Aaron J Schain, Robert A Hill and Jaime Grutzendler doi:10.1038/nm.3495 A new technique that allows high-resolution in vivo imaging of myelinated fibers without the use of a fluorescent marker is described by Aaron Schain and colleagues. This label-free approach, which does not require histological or immunocytochemical staining, uses spectral confocal reflectance microscopy, can be performed on a conventional confocal microscope, and can be used for deep-tissue transcranial imaging up to 400 μm deep, longitudinally tracking fine changes in axonal myelination. It has potential for the in vivo analysis of normal myelin development, as well as demyelinating diseases of the CNS and peripheral nervous system. Top Advertisement Nature Clinical Collection on Hepatocellular carcinoma (HCC) This Clinical Collection covers key aspects of the pathogenesis and treatment of HCC, including insights into disease pathways and possible future therapeutic targets.  FREE online This activity is supported by an educational grant from Lilly.   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. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.