Nature Medicine Contents: June 2014 Volume 20 Number 6 pp 561-688

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Advertisement A*STAR Research - Highlighting the best of research at the Agency for Science, Technology and Research (A*STAR), Singapore's premier research organization   Recent Highlights Drug delivery: A 'click' toward localized chemotherapy | Cancer surgery: Lighting up lymph nodes | Ophthalmology: Grading cataracts automatically Download the A*STAR Research app now!  TABLE OF CONTENTS June 2014 Volume 20, Issue 6 Editorial News Book Review Correspondence News and Views Between Bedside and Bench Research Highlights Brief Communication Articles Letters Technical Reports Advertisement   An Atlas of Genetic Influences on Human Blood Metabolites New publication in Nature Genetics reveals how metabolomic profiling coupled with genomics data yields new insight into diseases, potential biomarkers and drug treatments. Hundreds of exceptionally strong associations between metabolites and genetic variants have now been unveiled. These associations potentially provide a better understanding of gene function and can be enormously helpful in teasing apart genetic differences to 'complete the picture' of biological understanding. "Metabolomics...an excellent way of understanding individual uniqueness and..." - Craig Venter Read more... Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Scientific Data: Now Live  Scientific Data is an open-access, peer-reviewed publication and exists to help you publish, discover and reuse research data. It is now live so go visit nature.com/scientificdata to discover more and view our Data Descriptors.    Nature Medicine Podcast  Top Young Blood We discuss the revitalizing effects of young blood and how exome sequencing could help guide personalized cancer treatments. Listen Now Editorial Top Stay the course   p561 doi:10.1038/nm.3608 Key stakeholders, journals and funders must enable the additional research and early data sharing needed to advance the adoptive T cell therapy field as a whole. News Top First Chinese-made biologics slated for human trials in the West   p562 Boer Deng doi:10.1038/nm0614-562 Cryptographic methods enable analyses without privacy breaches   p563 Nicholette Zeliadt doi:10.1038/nm0614-563 Patent-free pact pushes the boundaries of precompetitive research   pp564 - 565 Elie Dolgin doi:10.1038/nm0614-564 New platforms aim to obliterate silos of participatory science   pp565 - 566 Elie Dolgin doi:10.1038/nm0614-565 Diabetes researchers fear worsening access to human islets   p567 Shraddha Chakradhar doi:10.1038/nm0614-567 Biomedical briefing   pp568 - 569 doi:10.1038/nm0614-568 Q&A Straight talk with...Geoffrey Ling   p570 doi:10.1038/nm0614-570 In April, the US Defense Advanced Research Projects Agency (DARPA) launched the Biological Technologies Office. The man picked to lead the BTO is Geoffrey Ling, a physician-scientist with training in neurology and pharmacology who spent 27 years in the US Army Medical Corps. Ling spoke with Brendan Borrell about what the BTO will mean for the medical research community. News Feature The cancer-virus cures   pp571 - 574 David Holmes doi:10.1038/nm0614-571 About 90% of the people in the world carry a latent virus known to cause cancer. On the fiftieth anniversary of its discovery, researchers are considering joining up their experimental treatments against these malignancies. David Holmes reports. Opinion Mentorship matters for the biomedical workforce   p575 Sally J Rockey doi:10.1038/nm0614-575 The mentorship of early-career scientists is necessary to their individual career success and the future of the biomedical research enterprise as a whole. Recently launched NIH programs and tools aim to facilitate this important type of training. Book Review Top Our antigens, our selves   p576 Alison Farrell reviews The Compatibility Gene: How Our Bodies Fight Disease, Attract Others, and Define Our Selves by Daniel M. Davis doi:10.1038/nm.3591 Correspondence Top NGS library preparation may generate artifactual integration sites of AAV vectors   pp577 - 578 Benjamin Cogne, Richard Snyder, Pierre Lindenbaum, Jean-Baptiste Dupont, Richard Redon et al. doi:10.1038/nm.3578 Reply to: NGS library preparation may generate artifactual integration sites of AAV vectors   pp578 - 579 Christine Kaeppel, Stuart G Beattie, Raffaele Fronza, Richard van Logtenstein, Florence Salmon et al. doi:10.1038/nm.3584 News and Views Top Interleukin-35 takes the 'B' line   pp580 - 581 Claudia Mauri and Kiran Nistala doi:10.1038/nm.3594 Regulatory B cells exert an immunosuppressive role by secreting the cytokine interleukin-10 (IL-10). Two studies have now identified B cell-derived IL-35 as both an inducer and a mediator of regulatory B cell function. IL-35 switched off inflammation in mouse models of autoimmunity, whereas its absence in B cells in mice enhanced survival after Salmonella enterica serovar Typhimurium infection. IL-35 could therefore be targeted for treating human autoimmune and infectious disease. See also: Article by Wang et al. Young blood rejuvenates old brains   pp582 - 583 Steven M Paul and Kiran Reddy doi:10.1038/nm.3597 Age-related cognitive decline occurs in many mammals, including humans, resulting from a decline in hippocampal function, and it is associated with reduced synaptic plasticity in hippocampal circuits. In this issue of Nature Medicine, a new study shows that cognitive impairment observed in aged mice is largely reversible following exposure to the blood of young mice. See also: Letter by Villeda et al. Lessons from babies: inducing HIV-1 broadly neutralizing antibodies   pp583 - 585 Georgia D Tomaras and Barton F Haynes doi:10.1038/nm.3598 A new study in infants shows that broadly neutralizing antibodies (bNAbs) against HIV can be found early in life, demonstrating for the first time that these antibodies can be induced by the infant immune system. See also: Letter by Goo et al. Cardiomyopathy, mitochondria and Barth syndrome: iPSCs reveal a connection   pp585 - 586 Kunil K Raval and Timothy J Kamp doi:10.1038/nm.3592 Barth syndrome is a rare X-linked genetic disorder caused by mutations in the tafazzin (TAZ) gene that result in dilated cardiomyopathy, skeletal myopathy and neutropenia. Tafazzin has a mitochondrial function, and a new study using cardiomyocytes derived from induced pluripotent stem cells (iPSCs) from humans with Barth syndrome identifies increased mitochondrial reactive oxygen species (ROS) production as a key intermediate causing cardiac contractile dysfunction (pages 616-623). See also: Article by Wang et al. An alternative DNA damage pathway to apoptosis in hematological cancers   pp587 - 588 John M Luk and Kun-Liang Guan doi:10.1038/nm.3593 Although hematological cancers are genomically unstable, the mechanisms by which they evade DNA damage-induced cell death are largely unknown. A current study has revealed that the Hippo signaling pathway transcriptional regulator YAP1 activates an ABL1/p73-mediated proapoptotic effect in response to DNA damage, suggesting that YAP1 has a tumor suppressor function and that the Hippo pathway is a potential therapeutic target in human cancers. See also: Article by Cottini et al. Nature Medicine JOBS of the week Assistant or Associate Professor of Medicine Columbia University Medical Center Postdoctoral Fellowship - The Johns Hopkins University School of Medicine Johns Hopkins University Group Leader Position, Molecular Medicine Paris Descartes University Clinical Investigator Scientist University of Cambridge More Science jobs from Nature Medicine EVENT Palliative Medicine Symposium 18.09.14 Nevada, USAA More science events from Between Bedside and Bench Top Overcoming Drug Development Bottlenecks With Repurposing: Old drugs learn new tricks   pp590 - 591 Stephen M Strittmatter doi:10.1038/nm.3595 The development of new therapies is an arduous, time-consuming and costly task. Furthermore, the development of many compounds runs into issues related to safety. Drug repurposing, where drugs with established safety in humans are tested and developed for efficacy in a disease other than the one for which they were developed, is gaining traction because of its potential to overcome an initial bottleneck in the drug development process. In [ldquo]Bedside to Bench,[rdquo] Stephen Strittmatter discusses the types of scenario in which drug repurposing may be of benefit, such as when a drug is repurposed for a new molecular target or for the same target in a different disease. In [ldquo]Bench to Bedside,[rdquo] Michael Pollak focuses on a recent study that suggest that biguanides that are normally used in the treatment of diabetes could have direct cyotoxic action on cancer cells with mutations in respiratory complex I. The pharmacokinetic hurdles that may need to be overcome for this to be translated to the clinic are also discussed. Overcoming Drug Development Bottlenecks With Repurposing: Repurposing biguanides to target energy metabolism for cancer treatment   pp591 - 593 Michael Pollak doi:10.1038/nm.3596 Research Highlights Top Cancer: Risky Y chromosome loss | Cancer immunotherapy: Personalized T cells fight cancer | Obesity: Recruiting inflammatory cells to fat | Monocytes and macrophages: Tissue control of macrophages | Cardiac hypertrophy: A miRNA star in the heart | Neuronal development: Environmental brain protection | Dengue virus: An enhanced model for dengue virus Brief Communication Top The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma   pp596 - 598 Chen Liu, Rachid Karam, YingQi Zhou, Fang Su, Yuan Ji et al. doi:10.1038/nm.3548 Pancreatic adenosquamous carcinomas are rare but highly aggressive tumors, and our understanding of them is limited. In a new study, Miles Wilkinson and colleagues now report that they have identified somatic mutations in an RNA helicase encoded by UPF1 in some pancreatic adenosquamous carcinomas. UPF1 is required for nonsense-mediated RNA decay, suggesting that the aberrant accumulation of altered RNA transcripts may contribute to the malignant phenotype of these tumors and could be a target of diagnostic and therapeutic approaches for this tumor type. Articles Top Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers   pp599 - 606 Francesca Cottini, Teru Hideshima, Chunxiao Xu, Martin Sattler, Martina Dori et al. doi:10.1038/nm.3562 Tumor cells of epithelial origin present rampant DNA damage but do not undergo apoptosis due to inactivation of TP53. Understanding the mechanisms by which tumor cells are protected from cell death is crucial for identifying new therapeutic targets. Cottini et al. report that hematological malignancies also present DNA damage and a distinct, TP53-independent mechanism for evading cell death: low levels of the Hippo pathway coactivator YAP1 prevent apoptosis induced by nuclear relocalization of ABL1 triggered by DNA damage. A serine-threonine kinase, STK4, downregulates YAP1 levels; notably, STK4 inhibition increases YAP1 and related p73-mediated apoptosis in hematological malignancies. See also: News and Views by Luk & Guan Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors   pp607 - 615 Gregory T Motz, Stephen P Santoro, Li-Ping Wang, Tom Garrabrant, Ricardo R Lastra et al. doi:10.1038/nm.3541 Tumors use numerous mechanisms to escape detection and killing by the immune system. George Coukos and colleagues now report that cancer cells can also co-opt tumor-associated endothelial cells to prevent immune eradication. The researchers show that factors secreted by cancer cells induce increased expression of Fas ligand on the tumor endothelium, resulting in killing of CD8+ effector T cells and thereby facilitating immune escape and tumor growth. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies   pp616 - 623 Gang Wang, Megan L McCain, Luhan Yang, Aibin He, Francesco Silvio Pasqualini et al. doi:10.1038/nm.3545 Cardiomyocytes generated from induced pluripotent cells hold great promise for understanding and treating heart disease. William Pu and his colleagues apply new technologies for studying such cardiomyocytes from patients with Barth syndrome to explore how the mitochondrial defects characteristic of this syndrome lead to heart dysfunction. See also: News and Views by Raval & Kamp Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia   pp624 - 632 TingTing Hong, Huanghe Yang, Shan-Shan Zhang, Hee Cheol Cho, Mariya Kalashnikova et al. doi:10.1038/nm.3543 In heart muscle cells, a region of the sarcolemmal membrane periodically invaginates to form T tubules, a specialized membrane domain that contains important ion channels regulating cell contraction. Robin Shaw and his colleagues describe how a cardiac-specific splice variant of the isoform of the protein BIN1 helps make folds in T tubules, which affects the ability of ions in the extracellular space to freely diffuse and protects the heart from arrhythmia. Interleukin-35 induces regulatory B cells that suppress autoimmune disease   pp633 - 641 Ren-Xi Wang, Cheng-Rong Yu, Ivy M Dambuza, Rashid M Mahdi, Monika B Dolinska et al. doi:10.1038/nm.3554 Regulatory B (Breg) cells producing interleukin-10 (IL-10) suppress autoimmune disease, but the mechanisms mediating their induction remain unclear. Charles E. Egwuagu and colleagues report that IL-35 induces Breg cells and also promotes their production of IL-35. In vivo IL-35 suppresses autoimmune disease in an IL-35 receptor- and IL-10-dependent manner. Adoptive transfer of IL-35-induced Breg cells inhibits established autoimmune disease, suggesting that IL-35 and IL-35-producing Breg cells may be used to treat inflammatory disease. See also: News and Views by Mauri & Nistala Letters Top Lung microbiota promotes tolerance to allergens in neonates via PD-L1   pp642 - 647 Eva S Gollwitzer, Sejal Saglani, Aurelien Trompette, Koshika Yadava, Rebekah Sherburn et al. doi:10.1038/nm.3568 The immune system matures during the neonatal period and is influenced by environmental factors. Benjamin J. Marsland and his colleagues show that the lung is colonized by microbes early in life. Formation of the lung microbiota is associated with the induction of regulatory T cells and the development of tolerance to allergens. Absence of microbial colonization leads to allergic airway disease later in life, suggesting that the lung microbiota promotes immune tolerance. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage   pp648 - 654 Lukas Schwab, Luise Goroncy, Senthilnathan Palaniyandi, Sanjivan Gautam, Antigoni Triantafyllopoulou et al. doi:10.1038/nm.3517 Although neutrophils have crucial functions in microbial killing, they can also trigger tissue damage via the release of reactive oxygen species and proinflammatory mediators. Robert Zeiser and colleagues now report that neutrophils also contribute to the severity of graft-versus-host disease following translocation of bacteria in the gut induced by the conditioning regimen for allogeneic hematopoietic cell transplantation. Early development of broadly neutralizing antibodies in HIV-1-infected infants   pp655 - 658 Leslie Goo, Vrasha Chohan, Ruth Nduati and Julie Overbaugh doi:10.1038/nm.3565 Antibodies capable of neutralizing a broad array of HIV-1 viral isolates from different clades have been isolated from some chronically infected individuals, but their development is thought to require several years. In this issue, Julie Overbaugh and her colleagues report that HIV-infected infants also develop broadly neutralizing antibodies[mdash]some at 1 year of age[mdash]and their occurrence early in life may shed light on HIV vaccine efforts to induce these antibodies. See also: News and Views by Tomaras & Haynes Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice   pp659 - 663 Saul A Villeda, Kristopher E Plambeck, Jinte Middeldorp, Joseph M Castellano, Kira I Mosher et al. doi:10.1038/nm.3569 Aging is associated with cognitive impairment and degenerative processes in the brain. Here, Tony Wyss-Coray and colleagues report that exposure of aged mice to young blood improves learning and memory in aged mice. This effect is associated with structural improvements in dendritic spine density in the hippocampus and functionally with increased synaptic plasticity. These findings suggest that circulating factors in young blood can reverse impairments in learning, memory and synaptic plasticity in aged mice. See also: News and Views by Paul & Reddy Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis   pp664 - 669 Phillip J White, Philippe St-Pierre, Alexandre Charbonneau, Patricia L Mitchell, Emmanuelle St-Amand et al. doi:10.1038/nm.3549 Lower levels of [omega]-3 fatty acid-derived resolution mediators have been linked to insulin resistance in obese mice. Andre Marette and his colleagues now show that treatment of obese mice with a resolution mediator (protectin DX (PDX)) results in IL-6 release from muscle and subsequent improvement in insulin sensitivity. PDX may represent a new class of antidiabetes medication. Excessive transforming growth factor-[beta] signaling is a common mechanism in osteogenesis imperfecta   pp670 - 675 Ingo Grafe, Tao Yang, Stefanie Alexander, Erica P Homan, Caressa Lietman et al. doi:10.1038/nm.3544 Osteogenesis imperfecta (OI) is a debilitating illness marked by brittle bones and fractures, as well as extraskeletal abnormalities. Now, Ingo Grafe and colleagues show that both the dominant and recessive forms of this disease are caused by excessive TGF-[beta] signaling and that targeting this pathway improves bone health in mouse models of OI. Technical Reports Top Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice   pp676 - 681 Hong Qin, Beatrisa Lerman, Ippei Sakamaki, Guowei Wei, Soungchul C Cha et al. doi:10.1038/nm.3560 Using an adapted competitive peptide phage display platform, Hong Qin and colleagues identify new candidate peptides specifically binding myeloid-derived suppressor cells (MDSCs), with which they generate peptide-Fc fusion proteins (peptibodies). The peptibodies deplete intra-umoral MDSCs in several mouse tumor models, in addition to those in blood and spleen, with limited off-target activity and superiority over standard depletion methods. Validation of this approach for cell type-specific surface marker discovery identified S100A9 as a target on the surface of MDSCs. Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine   pp682 - 688 Eliezer M Van Allen, Nikhil Wagle, Petar Stojanov, Danielle L Perrin, Kristian Cibulskis et al. doi:10.1038/nm.3559 Whole-exome sequencing (WES) has emerged as a transformative technology for biological discovery, but technical difficulties have so far prevented its widespread clinical use. Here, Eliezer Van Allen and colleagues are able to perform production-scale WES on small amounts of clinically acquired formalin-fixed, paraffin-embedded tumor tissues. Using a newly created WES clinical interpretation algorithm, they apply the complete clinical WES framework prospectively to patients and demonstrate how it can be used to directly affect patient care. Top Advertisement Nature Outlook Antibiotics Antibiotic-resistant infections are increasing worldwide. As this Outlook reveals, it will take agricultural and healthcare reforms to defeat the encroaching bacterial epidemic.  Access the Outlook free online for six months. Produced with support from Roche.    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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