Table of contents


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Editorial

The dangers of the fast track p389

doi:10.1038/nm0411-389

The US Food and Drug Administration (FDA) wants to create a way to fast-track approval of new medical devices, but they must first address the problems of the existing accelerated process for bringing devices to market that are substantially equivalent to ones already in commercial distribution.


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News

Nuclear leak reinforces need for drugs to combat radiation p391

Cassandra Willyard

doi:10.1038/nm0411-391


Trial success spurs planning for rollout of HIV prevention pills p392

Elie Dolgin

doi:10.1038/nm0411-392


Trial in youngest group points to HIV treatment overhaul p393

Elie Dolgin

doi:10.1038/nm0411-393


New organization pledges scientific expertise for viral outbreaks p394

Adam Mann

doi:10.1038/nm0411-394a


UK plans 30% funding bump for translational research p394

Bea Perks

doi:10.1038/nm0411-394b


Speedy sequencing technologies help track food-borne illness p395

Michelle Pflumm

doi:10.1038/nm0411-395a


Drugs development is cheaper than widely claimed, experts say p395

Michelle Pflumm

doi:10.1038/nm0411-395b


Mutation-specific cystic fibrosis treatments on verge of approval pp396 - 397

Elie Dolgin

doi:10.1038/nm0411-396


Orphan cystic fibrosis drugs find sister diseases p397

Elie Dolgin

doi:10.1038/nm0411-397


Genetic insights beginning to divide autism diagnosis p398

Monica Heger

doi:10.1038/nm0411-398a


France promotes research into rare diseases with new plan pp398 - 399

Barbara Casassus

doi:10.1038/nm0411-398b


Sequencing reveals suite of commensal and pathogenic viruses p399

Elie Dolgin

doi:10.1038/nm0411-399


After half-century's wait, approval paves path for new lupus drugs p400

Heidi Ledford

doi:10.1038/nm0411-400a


Pooled trials drowning in conflict-of-interest oversights pp400 - 401

Nazlie Latefi

doi:10.1038/nm0411-400b


African genomics project takes shape at Cape Town meeting p401

Linda Nordling

doi:10.1038/nm0411-401


News in brief: Biomedical briefing pp402 - 403

doi:10.1038/nm0411-402


Straight talk with...Seth Berkley p404

Roxanne Khamsi

doi:10.1038/nm0411-404

It was announced last month that Seth Berkley, who founded and heads the International AIDS Vaccine Initiative (IAVI), will take over the helm of the GAVI Alliance in August. Berkley, an epidemiologist who previously held jobs with the Rockefeller Foundation, the Carter Center and the US Centers for Disease Control and Prevention, has witnessed ups and downs in the vaccination field, from the disappointing STEP trial in 2007 to the more recent good news from the 2009 Thai study, which reported as much as 31% protection against HIV. Roxanne Khamsi spoke with Berkley about what he has learned in his quest for a preventative shot against AIDS.


Mutations to the rescue pp405 - 407

Mike May

doi:10.1038/nm0411-405

Genetic mutations are usually the source of debilitating disease. But, for a number of rare inherited blood and skin disorders, spontaneous DNA changes can repair and even reverse disease symptoms. Mike May explores the therapeutic potential of this 'natural gene therapy'.


Missed connections pp408 - 410

Marissa Miley

doi:10.1038/nm0411-408

A surprising percentage of people with autism also suffer from seizures, but doctors have been baffled by this overlap for decades. Now, various groups of scientists have begun exploring how the same genetic risk factors and aberrations in nerve signaling in early brain development might underlie both these disorders. Marissa Miley reports on how solving this riddle could point to better treatments for epilepsy and autism.


Opinion

Engage with, don't fear, community labs p411

Ellen D Jorgensen & Daniel Grushkin

doi:10.1038/nm0411-411

The do-it-yourself biology movement has exploded in recent years, culminating in the formation of the world's first community laboratory, opened late last year. As this grassroots effort continues to grow, professional biomedical researchers stand to benefit from partnering with the legions of garage biotechnology enthusiasts.


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Book Review

That obscure object of desire p412

Jan Vijg reviews The Youth Pill: Scientists at the Brink of an Anti-Aging Revolution by David Stipp

doi:10.1038/nm0411-412


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Correspondence

The flip side of cardiolipin import p413

Coen C Paulusma, Roderick H J Houwen & Patrick L Williamson

doi:10.1038/nm0411-413a


Reply to "The flip side of cardiolipin import" pp413 - 414

Bill B Chen, Jian Fei Jiang, Nancy B Ray, Valerian E Kagan & Rama K Mallampalli

doi:10.1038/nm0411-413b


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News and Views

Alum's adjuvant action: grease is the word pp415 - 416

M Lamine Mbow, Ennio De Gregorio & Jeffrey B Ulmer

doi:10.1038/nm0411-415

Alum is the most widely used vaccine adjuvant, but its mechanism of action remains largely unknown. A recent study shows that alum interacts directly with membrane lipids on the surface of dendritic cells, triggering signaling cascades that promote CD4+ T cell activation and humoral immune responses (pages 479–487).

See also: Article by Flach et al.


Trastuzumab resistance: all roads lead to SRC pp416 - 418

Senthil K Muthuswamy

doi:10.1038/nm0411-416

A new study shows how SRC, a nonmembrane tyrosine kinase, is a common signaling node in trastuzumab resistance caused by different mechanisms in HER2-positive breast cancers (pages 461–469). A SRC inhibitor restored trastuzumab sensitivity in vitro and in mouse tumor models, suggesting a new way to tackle drug resistance in breast tumors.

See also: Article by Zhang et al.


An amino acid profile to predict diabetes? pp418 - 420

Claudia Langenberg & David B Savage

doi:10.1038/nm0411-418

By the time diabetes is diagnosed, irreversible pathology is typically present, challenging therapeutic intervention. A reliable test for predicting diabetes risk could allow earlier implementation of intervention measures. Increased blood concentrations of amino acids are now suggested to predict risk of diabetes (pages 448–453), and amino acid profiling might also provide mechanistic insights into this disease.

See also: Article by Wang et al.


Derailing heterotopic ossification and RARing to go pp420 - 421

Frederick S Kaplan & Eileen M Shore

doi:10.1038/nm0411-420

Retinoic acid receptors inhibit chondrogenesis, but their ability to block the cartilaginous scaffold of heterotopic endochondral ossification has not been explored. A study in mice shows that agonists of retinoic acid receptor-γ potently inhibit heterotopic endochondral ossification, suggesting therapeutic potential in people with this condition (pages 454–460).

See also: Article by Shimono et al.


A new treasure in the breast cancer gene hunt pp422 - 423

Paul Spellman & Joe Gray

doi:10.1038/nm0411-422

A new potential breast cancer oncogene, ZNF703, has been identified in the chromosomal region 8p12 in humans, which is commonly amplified in an aggressive subtype of breast cancer. ZNF703 is a transcriptional repressor and regulates many genes that are involved in multiple aspects of the cancer phenotype, such as increased proliferation, invasion and an altered balance of progenitor stem cells.


Axonal injury in reverse pp423 - 426

Matt J Craner & Lars Fugger

doi:10.1038/nm0411-423

Axonal damage causes neurological defects in multiple sclerosis. In vivo imaging in mouse models of multiple sclerosis now shows a reversible and sequential process of focal axonal degeneration (FAD) (pages 495–499), suggesting the use of neuroregenerative as well as neuroprotective drugs as potential therapies for multiple sclerosis.

See also: Letter by Nikić et al.


A Src link in schizophrenia pp425 - 427

Chang-Gyu Hahn

doi:10.1038/nm0411-425

A new study shows that a candidate schizophrenia pathway, neuregulin-1–ErbB4 signaling, inhibits Src-mediated enhancement of synaptic N-methyl-D-aspartate receptor (NMDAR) function (pages 470–478). These results suggest that Src can have a pivotal role in NMDAR hypofunction in schizophrenia and thus might have potential therapeutic implications for this complex neuropsychiatric disorder.

See also: Article by Pitcher et al.


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Between Bedside and Bench

The bone and beyond: 'Dem bones' are made for more than walking pp428 - 430

L Darryl Quarles

doi:10.1038/nm0411-428

Bone is an endocrine organ that reaches out to other tissues, orchestrating responses that may have a role in pathology and physiology at distant sites. In 'Bench to Bedside', L. Darryl Quarles discusses recent studies showing how a feedback loop between the bone hormone FGF-23 and renal phosphate excretion and vitamin D metabolism is integrated with the classical PTH–vitamin D axis in chronic kidney disease (CKD). This new paradigm may change the diagnosis and treatment of disordered mineral homeostasis of people with CKD. A recent epidemiological study argues a mechanistic link between bone loss and atherosclerosis, maladies usually linked to aging. In 'Bedside to Bench', Sundeep Khosla discusses how this clinical study underpins research showing that mediators of inflammation and oxidative stress share common mechanisms that may lead to this calcium shift during aging.


The bone and beyond: A shift in calcium pp430 - 431

Sundeep Khosla

doi:10.1038/nm0411-430


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Commentaries

Enhancing ties between academia and industry to improve health pp434 - 436

S Claiborne Johnston, Stephen L Hauser & Susan Desmond-Hellmann

doi:10.1038/nm0411-434


Time to 'walk the walk' about industry ties to enhance health pp437 - 438

Thomas P Stossel & Lance K Stell

doi:10.1038/nm0411-437


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Review

The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease pp439 - 447

Jens P Dreier

doi:10.1038/nm.2333

Brain injury, subarachnoid hemorrhage and the subsequent delayed ischemic stroke show spreading depolarization of neurons in the tissue at risk, where it leads to spreading ischemia, vasoconstriction and brain electrical silencing, exacerbating damage and thwarting recovery. Jens Dreier reviews the underlying molecular mechanisms and the potential use for clinical diagnosis and therapies aimed at blocking spreading depolarization and boosting vasodilation to treat neurological disease.


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Articles

Metabolite profiles and the risk of developing diabetes pp448 - 453

Thomas J Wang, Martin G Larson, Ramachandran S Vasan, Susan Cheng, Eugene P Rhee, Elizabeth McCabe, Gregory D Lewis, Caroline S Fox, Paul F Jacques, Céline Fernandez, Christopher J O'Donnell, Stephen A Carr, Vamsi K Mootha, Jose C Florez, Amanda Souza, Olle Melander, Clary B Clish & Robert E Gerszten

doi:10.1038/nm.2307

Amino acid profiles could aid in diabetes risk assessment, as a five-amino-acid signature had highly significant associations with the development of future diabetes in two large, independent cohorts.

See also: News and Views by Langenberg & Savage


Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists pp454 - 460

Kengo Shimono, Wei-en Tung, Christine Macolino, Amber Hsu-Tsai Chi, Johanna H Didizian, Christina Mundy, Roshantha A Chandraratna, Yuji Mishina, Motomi Enomoto-Iwamoto, Maurizio Pacifici & Masahiro Iwamoto

doi:10.1038/nm.2334

Heterotopic ossification is the conversion of soft tissue into bone, usually after surgery or trauma but also as a result of the genetic disease fibrodysplasia ossificans progressiva. Masahiro Iwamoto and his colleagues have now shown that retinoic receptor-γ agonists ameliorate this condition in mouse models.

See also: News and Views by Kaplan & Shore


Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways pp461 - 469

Siyuan Zhang, Wen-Chien Huang, Ping Li, Hua Guo, Say-Bee Poh, Samuel W Brady, Yan Xiong, Ling-Ming Tseng, Shau-Hsuan Li, Zhaoxi Ding, Aysegul A Sahin, Francisco J Esteva, Gabriel N Hortobagyi & Dihua Yu

doi:10.1038/nm.2309

This report uncovers that activation of Src lies downstream of multiple trastuzumab-resistance–driving pathways. The authors show that Src, a major mediator of PI3K and IGFR resistance pathways, also drives resistance caused by PTEN loss, revealing that Src is directly dephosphorylated by PTEN. Src inhibition can overcome de novo and acquired trastuzumab resistance, suggesting a potential therapeutic strategy broadly applicable in breast cancer.

See also: News and Views by Muthuswamy


Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors pp470 - 478

Graham M Pitcher, Lorraine V Kalia, David Ng, Nathalie M Goodfellow, Kathleen T Yee, Evelyn K Lambe & Michael W Salter

doi:10.1038/nm.2315

Schizophrenia has been associated with overactive neuregulin signaling and with glutamatergic synaptic hypoactivity. Now, in brain slice culture experiments, Michael Salter and his colleagues show that neuregulin signaling interferes with Src-induced activation of glutamatergic synaptic activity.

See also: News and Views by Hahn


Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity pp479 - 487

Tracy L Flach, Gilbert Ng, Aswin Hari, Melanie D Desrosiers, Ping Zhang, Sandra M Ward, Mark E Seamone, Akosua Vilaysane, Ashley D Mucsi, Yin Fong, Elmar Prenner, Chang Chun Ling, Jurg Tschopp, Daniel A Muruve, Matthias W Amrein & Yan Shi

doi:10.1038/nm.2306

Alum has long been used as a vaccine adjuvant, yet the mechanisms by which it increases antigen-specific immune responses remain unclear. Flach et al. now report that alum interacts with lipids in the plasma membrane of dendritic cells, resulting in nonphagocytic uptake of antigen and increased association with CD4+ T cells. These results suggest that, at least for dendritic cells, lipids rather than proteins may sense alum and trigger downstream signaling events that lead to enhanced T cell responses.

See also: News and Views by Mbow et al.


RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis pp488 - 494

Rieko Muramatsu, Takekazu Kubo, Masahiro Mori, Yuka Nakamura, Yuki Fujita, Tsugio Akutsu, Tatsusada Okuno, Junko Taniguchi, Atsushi Kumanogoh, Mari Yoshida, Hideki Mochizuki, Satoshi Kuwabara & Toshihide Yamashita

doi:10.1038/nm.2321

Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that is involved in retinal development and neural tube closure. Toshihide Yamashita and colleagues describe a previously unrecognized role for RGMa in the immune system. Blockade of RGMa attenuates clinical symptoms of experimental autoimmune encephalomyelitis and reduces T cell proliferation and cytokine release. These results suggest a possible new therapeutic target for multiple sclerosis.


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Letters

A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis pp495 - 499

Ivana Nikić, Doron Merkler, Catherine Sorbara, Mary Brinkoetter, Mario Kreutzfeldt, Florence M Bareyre, Wolfgang Brück, Derron Bishop, Thomas Misgeld & Martin Kerschensteiner

doi:10.1038/nm.2324

Axonal degeneration is a hallmark of multiple sclerosis, but it remains unclear what triggers degeneration. By monitoring the development of axonal damage in a mouse model of multiple sclerosis, Ivana Nikić et al. describe a new variant of axonal degeneration. Axonal damage is present in myelinated axons and is reversible using scavengers of reactive oxygen and nitrogen species, thereby suggesting that early stages of degeneration may be amenable to therapeutic intervention.

See also: News and Views by Craner & Fugger


Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy pp500 - 503

Eric A Collisson, Anguraj Sadanandam, Peter Olson, William J Gibb, Morgan Truitt, Shenda Gu, Janine Cooc, Jennifer Weinkle, Grace E Kim, Lakshmi Jakkula, Heidi S Feiler, Andrew H Ko, Adam B Olshen, Kathleen L Danenberg, Margaret A Tempero, Paul T Spellman, Douglas Hanahan & Joe W Gray

doi:10.1038/nm.2344

This report describes the identification of three molecularly distinct subtypes of pancreatic ductal adenocarninoma (PDA). The classical, quasimesenchymal and exocrine subtypes can further stratify tumors with the same genetic alterations, and could be useful to improve prognosis and predict treatment response.


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Technical Reports

RGB marking facilitates multicolor clonal cell tracking pp504 - 509

Kristoffer Weber, Michael Thomaschewski, Michael Warlich, Tassilo Volz, Kerstin Cornils, Birte Niebuhr, Maike Täger, Marc Lütgehetmann, Jörg-Matthias Pollok, Carol Stocking, Maura Dandri, Daniel Benten & Boris Fehse

doi:10.1038/nm.2338

Kristoffer Weber et al. describe a new lentiviral vector-mediated RGB (red, green and blue) multicolor cell marking technique for analyzing clonal cell fates in vitro and in vivo. Here they use RGB marking to assess clonality after regeneration of injured livers by transplanted primary hepatocytes, to mark hematopoietic stem/progenitor cells and to assess the clonality of tumor cells. The approach can potentially be adapted to various cell types and other vector systems.


Fetal-specific DNA methylation ratio permits noninvasive prenatal diagnosis of trisomy 21 pp510 - 513

Elisavet A Papageorgiou, Alex Karagrigoriou, Evdokia Tsaliki, Voula Velissariou, Nigel P Carter & Philippos C Patsalis

doi:10.1038/nm.2312

Noninvasive testing for Down's syndrome (trisomy 21) would greatly reduce the risks associated with the more invasive techniques used currently. Earlier identification of differentially methylated regions between fetal DNA and maternal peripheral blood has now enabled Elisavet Papageorgiou and her colleagues to develop a strategy involving methylated DNA immunoprecipitation in combination with real-time quantitative PCR that discriminates normal from trisomy 21 cases in maternal peripheral blood with high sensitivity.


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Errata

Erratum: Cancer drugs: remedy required p514

doi:10.1038/nm0411-514a


Erratum: Hugging tight in Huntington's p514

Ashu Johri, Rajnish K Chaturvedi & M Flint Beal

doi:10.1038/nm0411-514b


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Corrigenda

Corrigendum: Hugging tight in Huntington's p514

Ashu Johri, Rajnish K Chaturvedi & M Flint Beal

doi:10.1038/nm0411-514c


Corrigendum: Conversion of vascular endothelial cells into multipotent stem-like cells p514

Damian Medici, Eileen M Shore, Vitali Y Lounev, Frederick S Kaplan, Raghu Kalluri & Bjorn R Olsen

doi:10.1038/nm0411-514d


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