Table of contents


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Editorial

The persistence of polio p323

doi:10.1038/nm.2708

Despite intense efforts to rid the world of poliovirus, it continues to persevere. Given the serious limitations of the existing vaccines, the feasibility of eradication must be reassessed.


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News

NIH accused of being overly literal on stem cell approvals p325

Elie Dolgin

doi:10.1038/nm0312-325


Genomics contest underscores challenges of personalized medicine p326

Megan Scudellari

doi:10.1038/nm0312-326


Trial designs for vaccines adapt to the times p327

Elie Dolgin

doi:10.1038/nm0312-327


Limb-saving medicines sought to prevent amputations p328

Cassandra Willyard

doi:10.1038/nm0312-328


Korea okays stem cell therapies despite limited peer-reviewed data p329

D Yvette Wohn

doi:10.1038/nm0312-329a


Survey says: too many PhDs p329

Rebecca Hersher

doi:10.1038/nm0312-329b


Small biotechs raring to cash in on the orphan disease market pp330 - 331

Rebecca Hersher

doi:10.1038/nm0312-330


New blood-boosting drugs aim to staunch renal anemia p332

Melinda Wenner Moyer

doi:10.1038/nm0312-332a


India opens malaria vaccine center pp332 - 333

Killugudi Jayaraman

doi:10.1038/nm0312-332b


Indian TB cases highlight need for drug-resistance tests p333

Rebecca Hersher

doi:10.1038/nm0312-333


Nodding syndrome leaves baffled scientists shaking their heads p334

Sarah C P Williams

doi:10.1038/nm0312-334


Q&A

Straight talk with... Robert Beall p335

Elie Dolgin

doi:10.1038/nm0312-335

When Robert J. Beall joined the Cystic Fibrosis Foundation in 1980, he launched a program aimed at absorbing the early financial risk involved in drug development as a way to entice for-profit companies to get involved in cystic fibrosis research. That strategy was vindicated with the approval in January of the first small-molecule drug that directly interacts with the mutated protein responsible for cystic fibrosis. Elie Dolgin spoke with Beall to learn more about his organization’s pioneering approach to venture philanthropy.


News in Brief

Biomedical briefing pp336 - 337

doi:10.1038/nm0312-336


Correction p337

doi:10.1038/nm0312-337


News Feature

Diagnosis by default pp338 - 340

Roxanne Khamsi

doi:10.1038/nm0312-338

Brain scans that map differences in how brain regions communicate while people lie idle in the imaging machine could one day provide clues about afflictions ranging from Alzheimer's disease to attention disorders. Roxanne Khamsi finds out why these so-called 'resting state' scans have made researchers and drug companies sit up and take notice.


Opinion

Public-private partnerships need honest brokering p341

Michel Goldman

doi:10.1038/nm0312-341

Given the current challenges in research and development, it's increasingly apparent that collaboration between large pharmaceutical companies, academic teams and biotechnology enterprises is essential for converting basic biomedical discoveries into lifesaving medicines. But these partnerships work best when a neutral third party helps foster them.


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Book Review

The obscure targets of desire p343

Garret A. FitzGerald reviews The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines by Brent R. Stockwell

doi:10.1038/nm.2696


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Correspondence

Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system pp344 - 346

Metamia Ciampricotti, Cheei-Sing Hau, Chris W Doornebal, Jos Jonkers & Karin E de Visser

doi:10.1038/nm.2652


HIV-1 Env antibodies: are we in a bind or going blind? pp346 - 347

John P Moore

doi:10.1038/nm.2689


Reply to: Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system p346

Laurence Zitvogel & Guido Kroemer

doi:10.1038/nm.2690


Reply to: HIV-1 Env antibodies: are we in a bind or going blind? pp347 - 348

Thomas J Hope

doi:10.1038/nm.2688


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News and Views

Chipping away at the lung cancer genome pp349 - 351

William Pao & Katherine E Hutchinson

doi:10.1038/nm.2697

Kinase inhibitors are now standard treatment for patients with lung cancer whose tumors harbor specific mutant kinases. Four recent studies, including three in this issue (pages 375–384), have identified new fusion proteins involving another receptor tyrosine kinase that may potentially be responsive to existing targeted therapies.

See also: Brief Communication by Kohno et al. | Brief Communication by Takeuchi et al. | Brief Communication by Lipson et al.


The AKTion in non-canonical insulin signaling pp351 - 353

Zhiyong Cheng & Morris F White

doi:10.1038/nm.2694

The kinase AKT has been regarded as an obligate intermediate in the insulin signaling pathway that suppresses glucose production by inhibiting the transcription factor forkhead box O1 (FoxO1) after meals. A new study shows that, without AKT-FoxO1 signaling, insulin still contributes to postprandial responses, revealing an AKT-independent pathway for insulin action that might be exploited to treat metabolic disease (pages 388–395).

See also: Article by Lu et al.


The quest for human ovarian stem cells pp353 - 354

Evelyn E Telfer & David F Albertini

doi:10.1038/nm.2699

Researchers have isolated a rare population of germline stem cells from adult mouse and human ovaries that are capable of forming oocytes. The ability to harvest such cells from human ovaries could change the options available for fertility preservation and the treatment of infertility (pages 413–421).

See also: Article by White et al.


Quantifying the activity of anti-HIV treatment in silico pp355 - 356

Ruy M Ribeiro

doi:10.1038/nm.2698

Combination-based antiretroviral therapy has been very successful in preventing disease progression in HIV-infected individuals. However, a rational method for predicting the effect of a particular drug combination on clinical outcome is needed. A new study takes us closer to this goal by computationally predicting the inhibitory effects of combinations of three antiretroviral drugs (pages 446–451).

See also: Letter by Jilek et al.


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Community Corner

At the heart of the benefits of bariatric surgery pp358 - 359

doi:10.1038/nm0312-358


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Review

The cellular and signaling networks linking the immune system and metabolism in disease pp363 - 374

Olivia Osborn & Jerrold M Olefsky

doi:10.1038/nm.2627

This review highlights the importance of immunometabolism to obesity and metabolic diseases such as diabetes. The authors describe recent advances in dissecting the cellular and signaling networks that link the immune and metabolic systems together, and how these insights could be translated to develop new therapeutic strategies to combat metabolic disease.


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Brief Communications

KIF5B-RET fusions in lung adenocarcinoma pp375 - 377

Takashi Kohno, Hitoshi Ichikawa, Yasushi Totoki, Kazuki Yasuda, Masaki Hiramoto, Takao Nammo, Hiromi Sakamoto, Koji Tsuta, Koh Furuta, Yoko Shimada, Reika Iwakawa, Hideaki Ogiwara, Takahiro Oike, Masato Enari, Aaron J Schetter, Hirokazu Okayama, Aage Haugen, Vidar Skaug, Suenori Chiku, Itaru Yamanaka, Yasuhito Arai, Shun-ichi Watanabe, Ikuo Sekine, Seishi Ogawa, Curtis C Harris, Hitoshi Tsuda, Teruhiko Yoshida, Jun Yokota & Tatsuhiro Shibata

doi:10.1038/nm.2644

The authors report a new type of genetic alteration in lung adenocarcinoma. Fusions of KIF5B with RET kinase are found in 1–2% of lung cancer patients, segregate from other known alterations and can potentially be targeted using RET kinase inhibitors.

See also: News and Views by Pao & Hutchinson


RET, ROS1 and ALK fusions in lung cancer pp378 - 381

Kengo Takeuchi, Manabu Soda, Yuki Togashi, Ritsuro Suzuki, Seiji Sakata, Satoko Hatano, Reimi Asaka, Wakako Hamanaka, Hironori Ninomiya, Hirofumi Uehara, Young Lim Choi, Yukitoshi Satoh, Sakae Okumura, Ken Nakagawa, Hiroyuki Mano & Yuichi Ishikawa

doi:10.1038/nm.2658

Through an integrated screening system, the authors catalog ALK and ROS1 fusions in lung cancer and identify a new class of fusions involving KIF5B and RET that may represent new therapeutic targets in adenocarcinoma.

See also: News and Views by Pao & Hutchinson


Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies pp382 - 384

Doron Lipson, Marzia Capelletti, Roman Yelensky, Geoff Otto, Alex Parker, Mirna Jarosz, John A Curran, Sohail Balasubramanian, Troy Bloom, Kristina W Brennan, Amy Donahue, Sean R Downing, Garrett M Frampton, Lazaro Garcia, Frank Juhn, Kathy C Mitchell, Emily White, Jared White, Zac Zwirko, Tamar Peretz, Hovav Nechushtan, Lior Soussan-Gutman, Jhingook Kim, Hidefumi Sasaki, Hyeong Ryul Kim, Seung-il Park, Dalia Ercan, Christine E Sheehan, Jeffrey S Ross, Maureen T Cronin, Pasi A Jänne & Philip J Stephens

doi:10.1038/nm.2673

Using high-coverage targeted next-generation sequencing, this report provides a catalog of genetic alterations in colorectal and lung cancers, identifying previously unknown alterations, such as JAK2 mutations and KIF5B-RET fusions, that may represent druggable targets.

See also: News and Views by Pao & Hutchinson


Blockade of PDGFR-β activation eliminates morphine analgesic tolerance pp385 - 387

Yan Wang, Katherine Barker, Shanping Shi, Miguel Diaz, Bing Mo & Howard B Gutstein

doi:10.1038/nm.2633

Morphine loses its ability to fight pain after chronic use. Now, Howard Gutstein and his colleagues report that morphine induces release of PDGF, and blockade of PDGFR signaling can reestablish morphine analgesic efficacy in rats that have become tolerant.


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Articles

Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1 pp388 - 395

Mingjian Lu, Min Wan, Karla F Leavens, Qingwei Chu, Bobby R Monks, Sully Fernandez, Rexford S Ahima, Kohjiro Ueki, C Ronald Kahn & Morris J Birnbaum

doi:10.1038/nm.2686

The insulin signaling pathway regulating glucose homeostasis that has been well accepted is insulin-to-insulin receptor-to-IRS proteins-to-PI3K-to-Akt-to-Foxo1—a pathway that does not respond properly in states of insulin resistance, including type 2 diabetes. In a new study from Morris Birnbaum and colleagues, an alternative insulin signaling pathway has been uncovered, as mice with liver-specific deletion of Akt and Foxo1 still respond normally to nutritional cues and properly regulate glucose metabolism. Although the exact nature of this alternative pathway needs to be identified, the results should open many new avenues of exploration in the field of type 2 diabetes.

See also: News and Views by Cheng & White


Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis pp396 - 404

Hikaru Sugimoto, Valerie S LeBleu, Dattatreyamurty Bosukonda, Peter Keck, Gangadhar Taduri, Wibke Bechtel, Hirokazu Okada, William Carlson, Philippe Bey, Mary Rusckowski, Björn Tampe, Desiree Tampe, Keizo Kanasaki, Michael Zeisberg & Raghu Kalluri

doi:10.1038/nm.2629

BMP7 has been previously shown to protect against renal fibrosis. Raghu Kalluri and his colleagues have now identified activin-like kinase 3 (Alk3) as the key co-receptor for BMP7 in the kidney and have identified an orally available, small-peptide agonist of Alk3 that reduces established fibrosis in five animal models of kidney injury.


Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis pp405 - 412

Kazuhiro Maeda, Yasuhiro Kobayashi, Nobuyuki Udagawa, Shunsuke Uehara, Akihiro Ishihara, Toshihide Mizoguchi, Yuichiro Kikuchi, Ichiro Takada, Shigeaki Kato, Shuichi Kani, Michiru Nishita, Keishi Marumo, T John Martin, Yasuhiro Minami & Naoyuki Takahashi

doi:10.1038/nm.2653

In a new study, Yasuhiro Kobayashi and his colleagues show that noncanonical Wnt signaling regulates balanced osteoblast-induced osteoclastogenesis during normal physiology and that this pathway is perturbed in pathophysiological states, such as rheumatoid arthritis. These results explain further how osteoblasts cross-talk with preosteoclasts to ensure matched bone resorption with bone formation during skeletal homeostasis in the adult and also suggest a new target to treat arthritis.


Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women pp413 - 421

Yvonne A R White, Dori C Woods, Yasushi Takai, Osamu Ishihara, Hiroyuki Seki & Jonathan L Tilly

doi:10.1038/nm.2669

In 2004, a team led by Jonathan Tilly reported that mice contained oogonial stem cells (OSCs), suggesting that females may be able to generate new oocytes in adulthood—a concept that was, and still is, quite controversial even though those findings have since been replicated by others. In a new report, Tilly and colleagues now perfect the purification of mouse OSCs and, using this technique, they show that similar cells exist in women of reproductive age. They also show that the mouse and human OSCs are able to give rise to oocytes in vivo (in the case of the human cells after xenotransplantation into NOD-SCID mice), while also showing that the mouse OSCs can give rise to embryos after in vitro fertilization.

See also: News and Views by Telfer & Albertini


NKG2D signaling on CD8+ T cells represses T-bet and rescues CD4-unhelped CD8+ T cell memory recall but not effector responses pp422 - 428

Andrew Zloza, Frederick J Kohlhapp, Gretchen E Lyons, Jason M Schenkel, Tamson V Moore, Andrew T Lacek, Jeremy A O'Sullivan, Vineeth Varanasi, Jesse W Williams, Michael C Jagoda, Emily C Bellavance, Amanda L Marzo, Paul G Thomas, Biljana Zafirova, Bojan Polić, Lena Al-Harthi, Anne I Sperling & José A Guevara-Patiño

doi:10.1038/nm.2683

CD8+ T cells primed in the absence of CD4+ T cell help fail to develop a robust memory cell response. Zloza et al. now report that these CD4-unhelped CD8+ T cells can be rescued by activating their cell surface receptor NKG2D, which restores CD8+ T cell expansion and cytolytic activity during a recall response and protection in a mouse model of influenza infection.


USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma pp429 - 435

Pieter J A Eichhorn, Laura Rodón, Alba Gonzàlez-Juncà, Annette Dirac, Magüi Gili, Elena Martínez-Sáez, Claudia Aura, Ignasi Barba, Vicente Peg, Aleix Prat, Isabel Cuartas, Jose Jimenez, David García-Dorado, Juan Sahuquillo, Réné Bernards, José Baselga & Joan Seoane

doi:10.1038/nm.2619

TGF-β signaling is commonly aberrantly activated in gliomas and other tumors and can exert a pro-oncogenic function. The authors identify a new mechanism for upregulation of TGF-β signaling in cancer. The deubiquitinase USP15 is shown to be able to bind the TGF-β receptor complex, counteract its degradation and potentiate its stimulation of downstream mediators. USP15 is amplified in human glioblastoma and could represent a therapeutic target, as its downregulation impairs the growth of glioblastoma cells in vivo.


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Letters

Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL pp436 - 440

Giusy Della Gatta, Teresa Palomero, Arianne Perez-Garcia, Alberto Ambesi-Impiombato, Mukesh Bansal, Zachary W Carpenter, Kim De Keersmaecker, Xavier Sole, Luyao Xu, Elisabeth Paietta, Janis Racevskis, Peter H Wiernik, Jacob M Rowe, Jules P Meijerink, Andrea Califano & Adolfo A Ferrando

doi:10.1038/nm.2610

The authors apply reverse engineering of transcriptional networks to identify the main functional drivers of the pro-leukemic transcriptional activity of TLX1 and TLX3, transcription factors usually altered in T-ALL. The network analysis uncovers RUNX1 as a key mediator of the effects of TLX factors and, consistently, mutations in RUNX1 are found in human T-ALL.


High abundance of plasma cells secreting transglutaminase 2–specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions pp441 - 445

Roberto Di Niro, Luka Mesin, Nai-Ying Zheng, Jorunn Stamnaes, Michael Morrissey, Jane-Hwei Lee, Min Huang, Rasmus Iversen, M Fleur du Pré, Shuo-Wang Qiao, Knut E A Lundin, Patrick C Wilson & Ludvig M Sollid

doi:10.1038/nm.2656

IgA antibodies directed against tissue transglutaminase 2 (TG2) are used as a serological marker of celiac disease. Ludvig M. Sollid and his colleagues provide an unbiased and thorough characterization of the mucosal antibody response directly from the effector compartment. They report that TG2-specific plasma cells are expanded in the duodenal mucosa of individuals with celiac disease. Antibodies cloned from these cells are of high affinity, show a restricted repertoire and minimal somatic hypermutation, and do not inhibit TG2 enzymatic activity.


A quantitative basis for antiretroviral therapy for HIV-1 infection pp446 - 451

Benjamin L Jilek, Melissa Zarr, Maame E Sampah, S Alireza Rabi, Cynthia K Bullen, Jun Lai, Lin Shen & Robert F Siliciano

doi:10.1038/nm.2649

Antiretroviral drug combinations for the treatment of HIV-1 infection have been determined on the basis of clinical trial outcomes, but without clear insight into why certain combinations are superior to others. Robert Siliciano and his colleagues present a quantitative basis for determining efficacious antiretroviral drug combinations.

See also: News and Views by Ribeiro


Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases pp452 - 455

Alan J Russell, James J Hartman, Aaron C Hinken, Alexander R Muci, Raja Kawas, Lena Driscoll, Guillermo Godinez, Kenneth H Lee, David Marquez, William F Browne IV, Michael M Chen, David Clarke, Scott E Collibee, Marc Garard, Richard Hansen, Zhiheng Jia, Pu-Ping Lu, Hector Rodriguez, Khalil G Saikali, Julia Schaletzky, Vipin Vijayakumar, Daniel L Albertus, Dennis R Claflin, David J Morgans, Bradley P Morgan & Fady I Malik

doi:10.1038/nm.2618

Neuromuscular disease is often marked by insufficient neural activation of muscle activity, resulting in muscle weakness. Fady Malik and colleagues have developed an orally available small molecule that sensitizes muscles to neural activity by reducing the off rate of calcium binding to troponin C. They validate the therapeutic potential of this drug in vivo in a rat model of myasthenia gravis and show that treatment improves grip strength by 50%.


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Technical Reports

Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass pp456 - 462

Min Guan, Wei Yao, Ruiwu Liu, Kit S Lam, Jan Nolta, Junjing Jia, Brian Panganiban, Liping Meng, Ping Zhou, Mohammad Shahnazari, Robert O Ritchie & Nancy E Lane

doi:10.1038/nm.2665

Targeting mesenchymal stem cells (MSCs), progenitors of osteoblasts, to bone has been a long-standing goal but has had limited success so far. Here, Min Guan and her colleagues deliver a peptidomimetic integrin ligand against integrin α4β1 conjugated to the bone-seeking agent bisphosphonate alendronate as a means of attracting infused and/or endogenous MSCs to the bone surface to stimulate bone formation. The approach was tested in both xenotransplantation and immunocompetent mice, as well as in mouse models of trabecular bone loss induced by aging and estrogen deficiency (ovariectomy).


Self-assembling nanocomplexes by combining ferumoxytol, heparin and protamine for cell tracking by magnetic resonance imaging pp463 - 467

Mya S Thu, L Henry Bryant, Tiziana Coppola, E Kay Jordan, Matthew D Budde, Bobbi K Lewis, Aneeka Chaudhry, Jiaqiang Ren, Nadimpalli Ravi S Varma, Ali S Arbab & Joseph A Frank

doi:10.1038/nm.2666

There are currently no good ways to track human cells in vivo in a clinical setting using magnetic resonance imaging (MRI) based on superparamagnetic iron-oxide nanoparticles. Mya Thu and colleagues have introduced a simple magnetic cell labeling approach that combines three currently US Food and Drug Administration–approved drugs—ferumoxytol, heparin and protamine—to form self-assembling nanocomplexes of about 150 nm in size that effectively label cells for MRI. The approach was shown to effectively label three types of stem cells and two types of immune cells.


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