TABLE OF CONTENTS
| January 2013 Volume 19, Issue 1 |  | | |  |  Editorial
News
Book Review
News and Views
Community Corner
Research Highlights
Commentary
Perspective
Articles
Letter
Technical Report
| | | | | | | Advertisement |  | | | | | Editorial |  Top | |  | | When true enough is not good enough p1
doi:10.1038/nm.3061
A recent court ruling that favored freedom of speech over the authority of the US Food and Drug Administration (FDA) to regulate off-label drug promotion may have profound implications for the way drugs are marketed and, ultimately, for patients' interests.
| | News | Top | | | | Neglected diseases see few new drugs despite upped investment p2
Cassandra Willyard
doi:10.1038/nm0113-2
| | | | NIH will withhold grant money to enforce public-access policy p3
Susan Matthews
doi:10.1038/nm0113-3
| | | | Cell-based vaccines yield only modest advances for seasonal flu p4
Cassandra Willyard
doi:10.1038/nm0113-4
| | | | Pharma fines increase, but the pain is not felt on Wall Street p5
Susan Matthews
doi:10.1038/nm0113-5
| | | | No end in sight for telomerase-targeted cancer drugs p6
Sarah C P Williams
doi:10.1038/nm0113-6
| | | | As leukemia options grow, drugs jockey to be first-line therapies p7
Elie Dolgin
doi:10.1038/nm0113-7
| | | | Rapid antidepressant effects of ketamine ignite drug discovery p8
Elie Dolgin
doi:10.1038/nm0113-8
| | | | | Q&A | | | | Straight talk with...Stephen O'Brien p9
Elie Dolgin
doi:10.1038/nm0113-9
In December 2011, Stephen O'Brien stepped down as head of the US National Cancer Institute's Laboratory of Genomic Diversity and took up a three-year, $5 million 'megagrant' in Russia through a program started a year earlier by the Russian Ministry of Education and Science. O'Brien used his money to help launch the Theodosius Dobzhansky Center for Genome Bioinformatics at Saint Petersburg State University. On a trip back to the US, O'Brien spoke with Elie Dolgin about his new Russian center.
| | | | | News in Brief | | | | Biomedical briefing pp10 - 11
doi:10.1038/nm0113-10
| | | | | News Feature | | | | A universal problem pp12 - 14
Hannah Hoag
doi:10.1038/nm0113-12
Recent headlines have promised that a 'universal flu vaccine' may be within reach, pointing to antibodies that offer broad protection in animal studies. But the scientists behind this effort had to first overcome great skepticism from their peers—as well as an imperfect laboratory test. Hannah Hoag reports on one virologist's 20-year effort to challenge the tenets of the field.
| | | | | Opinion | | | | Poor definitions threaten drug trial safety in India p15
Nupur Chowdhury
doi:10.1038/nm0113-15
India has become a hotbed of clinical trials, but recent reports of safety lapses have prompted calls for better regulation in this area. Currently, trial requirements can be relaxed if doing so is in the 'public interest', but a clearer definition of what this means is needed before this provision should be used.
| | Book Review | Top | | | | Assigning proper credit p16
Martin J. Blaser reviews Experiment Eleven by Peter Pringle
doi:10.1038/nm.3041
| | News and Views | Top | | | | Stress heats up the adipocyte pp17 - 18
Ffolliott Martin Fisher and Eleftheria Maratos-Flier
doi:10.1038/nm.3058
Cells and tissues are often subjected to stressful environments that challenge homeostasis and can include oxidative, nutrient or metabolic stress. Cell survival requires the recruitment of stress pathways that 'defend' the internal homeostatic environment of the cell. Recent studies indicate that activation of some of these existing pathways is beneficial to whole-body metabolism. Now, mice with a muscle-specific autophagy deficiency are shown to adapt to stress through a newly discovered endocrine pathway involving fibroblast growth factor 21 (FGF21) (pages 83-92).
See also: Article by Kim et al. | | | | Initiating type I diabetes: new suspects in the lineup pp18 - 20
Remi J Creusot
doi:10.1038/nm.3044
Several physiological and pathological events taking place postnatally in or around the pancreatic islets of Langerhans have been implicated in the initiation of type 1 diabetes. A new study highlights the contribution of neutrophils and how they, together with B1a cells and plasmacytoid dendritic cells (pDCs), may start the autoimmune process (pages 65-73).
See also: Article by Diana et al. | | | | Dual role of immunomodulation by anticancer chemotherapy pp20 - 22
Michael R Shurin
doi:10.1038/nm.3045
The anticancer efficacy of conventional chemotherapies seems to be due, in part, to augmentation of the host immune reactivity. However, a new study reveals that two common chemotherapeutic agents, gemcitabine and 5-fluorouracil, can also activate immune regulatory cells, which stimulates the emergence of protumorigenic cytokines via inflammasome pathways, limiting the antitumor efficacy of the drugs (pages 57-64).
See also: Article by Bruchard et al. | | | | Alzheimer's γ-secretase under arrestin pp22 - 24
Michael S Wolfe
doi:10.1038/nm.3053
Production of the amyloid-b peptide in Alzheimer's disease by the γ-secretase complex can be regulated by certain G protein-coupled receptors. This regulation seems to be mediated by b-arrestin-2, whose expression was found to be elevated in Alzheimer's disease brains (pages 43-49).
See also: Article by Thathiah et al. | | | |  | Nature Medicine
JOBS of the week | | | | | | | |
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| | Community Corner | Top | | | | Unlocking the mysterious mechanisms of Myc pp26 - 27
doi:10.1038/nm.3060
| | Research Highlights | Top | | | | Cancer: Next-generation CML therapy | Cancer: A metabolic hub in cancer | Immunity: Two types of T cells | Neurodegeneration: α-Synuclein's sufficient | Neuroscience: Seizures after surgery | Inflammation: Stemming colitis | Hematopoietic system: Piquing platelet production | New from NPG | Commentary | Top | | | | Roadblocks to translational challenges on viral pathogenesis pp30 - 34
Steven Deeks, Christian Drosten, Louis Picker, Kanta Subbarao and JoAnn Suzich
doi:10.1038/nm.3050
Distinct roadblocks prevent translating basic findings in viral pathogenesis into therapies and implementing potential solutions in the clinic. An ongoing partnership between the Volkswagen Foundation and Nature Medicine resulted in an interactive meeting in 2012, as part of the “Herrenhausen Symposia” series. Current challenges for various fields of viral research were recognized and discussed with a goal in mind—to identify solutions and propose an agenda to address the translational barriers. Here, some of the researchers who participated at the meeting provide a concise outlook at the most pressing unmet research and clinical needs, identifying these key obstacles is a necessary step towards the prevention and cure of human viral diseases.
| | Perspective | Top | | | | The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine pp35 - 42
Paolo Bianco, Xu Cao, Paul S Frenette, Jeremy J Mao, Pamela G Robey, Paul J Simmons and Cun-Yu Wang
doi:10.1038/nm.3028
The term 'mesenchymal stem cells' is widely used, yet the capabilities and characteristics of these postnatal bone marrow stem cells still warrant further examination. A further understanding and clarification of the true potential of these mesenchymal stem cells is crucial for their appropriate exploitation in the clinic.
| | Articles | Top | | | | β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease pp43 - 49
Amantha Thathiah, Katrien Horre, An Snellinx, Elke Vandewyer, Yunhong Huang, Marta Ciesielska, Gerdien De Kloe, Sebastian Munck and Bart De Strooper
doi:10.1038/nm.3023
The mechanism whereby activation of G protein-coupled receptors (GPCRs) increase the production of amyloid-β (Aβ) peptide remains unclear. Here Bart De Strooper and colleagues show that the GPCR adaptor protein β-arrestin 2 promotes Aβ production by associating with APH-1A and increasing γ-secretase activity. Overexpression of β-arrestin 2 increases Aβ generation, whereas mice lacking β-arrestin 2 have reduced amyloid accumulation. Moreover, expression of β-arrestin 2 is elevated in individuals with Alzheimer's disease, suggesting a potential therapeutic target aimed at reducing amyloid production.
See also: News and Views by Wolfe | | | | Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer pp50 - 56
Sakari Vanharanta, Weiping Shu, Fabienne Brenet, A Ari Hakimi, Adriana Heguy, Agnes Viale, Victor E Reuter, James J-D Hsieh, Joseph M Scandura and Joan Massague
doi:10.1038/nm.3029
Whether the molecular drivers of tumor initiation are the same factors that promote metastasis during tumor progression is addressed in this report. In renal carcinoma, common primary driving alterations such as VHL loss do not necessarily correlate with outcome, and the authors show that additional epigenetic adaptations are required to unleash prometastatic behavior. Two important metastastic drivers, CXCR4 and CYTIP, are activated downstream of VHL loss through epigenetic reprogramming involving differential chromatin modification or DNA methylation, exemplifying the complex evolution of tumorigenic traits downstream of driving alterations.
| | | | Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth pp57 - 64
Melanie Bruchard, Gregoire Mignot, Valentin Derangere, Fanny Chalmin, Angelique Chevriaux, Frederique Vegran, Wilfrid Boireau, Benoit Simon, Bernhard Ryffel, Jean Louis Connat, Jean Kanellopoulos, Francois Martin, Cedric Rebe, Lionel Apetoh and Francois Ghiringhelli
doi:10.1038/nm.2999
Gemcitabine and 5-fluorouracil are two commonly used chemotherapeutic agents for the treatment of cancer. Francois Ghiringhelli and colleagues now report that the antitumor efficacy of these agents is mitigated by myeloid derived suppressor cells (MDSCs). The authors show that these drugs can activate the NLRP3 inflammasome, leading to increased secretion of IL-1β by MDSCs and IL-17 production by CD4+ T cells, which can promote tumor growth.
See also: News and Views by Shurin | | | | Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes pp65 - 73
Julien Diana, Yannick Simoni, Laetitia Furio, Lucie Beaudoin, Birgitta Agerberth, Franck Barrat and Agnes Lehuen
doi:10.1038/nm.3042
The early events in the pathogenesis of type 1 diabetes remain incompletely understood. Julien Diana et al. now show that in response to physiological beta cell death, innate immune cells including neutrophils and B1-a cells are recruited early on to pancreatic islets. These cells promote interferon-α production by plasmacytoid dendritic cells in the pancreas, promoting autoreactive T cell responses and autoimmunity.
See also: News and Views by Creusot | | | | An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension pp74 - 82
Jongmin Kim, Yujung Kang, Yoko Kojima, Janet K Lighthouse, Xiaoyue Hu, Micheala A Aldred, Danielle L McLean, Hyekyung Park, Suzy A Comhair, Daniel M Greif, Serpil C Erzurum and Hyung J Chun
doi:10.1038/nm.3040
Vascular homeostasis in the lung is disturbed in pulmonary arterial hypertension. Jongmin Kim et al. delineate a new signaling axis controlling endothelial cell proliferation and cytokine production that is dysregulated in pulmonary endothelial cells from individuals with this disease. In this axis, the peptide apelin controls expression of the cytokine FGF2, a mitogen for endothelial and vascular smooth-muscle cells, through effects on two microRNAs. The authors also demonstrated the functional importance of these miRNAs in rat models of pulmonary hypertension.
| | | | Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine pp83 - 92
Kook Hwan Kim, Yeon Taek Jeong, Hyunhee Oh, Seong Hun Kim, Jae Min Cho, Yo-Na Kim, Su Sung Kim, Do Hoon Kim, Kyu Yeon Hur, Hyoung Kyu Kim, TaeHee Ko, Jin Han, Hong Lim Kim, Jin Kim, Sung Hoon Back, Masaaki Komatsu, Hsiuchen Chen, David C Chan, Morichika Konishi, Nobuyuki Itoh, Cheol Soo Choi and Myung-Shik Lee
doi:10.1038/nm.3014
Defects in mitochondrial function have been believed to contribute to insulin resistance. Myung-Shik Lee and colleagues now show that mitochondrial dysfunction in muscle induced by tissue-specific deficiency of autophagy results in upregulation of Fgf21 and improved metabolism, suggesting that at least some mitochondrial dysfunction may actually be beneficial.
See also: News and Views by Fisher & Maratos-Flier | | | | miR-214 targets ATF4 to inhibit bone formation pp93 - 100
Xiaogang Wang, Baosheng Guo, Qi Li, Jiang Peng, Zhijun Yang, Aiyuan Wang, Dong Li, Zhibo Hou, Ke Lv, Guanghan Kan, Hongqing Cao, Heng Wu, Jinping Song, Xiaohua Pan, Qiao Sun, Shukuan Ling, Yuheng Li, Mu Zhu, Pengfei Zhang, Songlin Peng, Xiaoqing Xie, Tao Tang, An Hong, Zhaoxiang Bian, Yanqiang Bai, Aiping Lu, Yinghui Li, Fuchu He, Ge Zhang and Yingxian Li
doi:10.1038/nm.3026
In a new study Yingxian Li and her colleagues show that the microRNA miR-214 targets ATF4 in osteoblasts to negatively regulate their activity. Manipulating miR-214 levels experimentally showed that its elevated expression is sufficient to induce bone loss in mice and that its therapeutic inhibition reduces bone loss in two mouse models.
| | Letter | Top | | | | Activation of calcium signaling through Trpv1 by nNOS and peroxynitrite as a key trigger of skeletal muscle hypertrophy pp101 - 106
Naoki Ito, Urs T Ruegg, Akira Kudo, Yuko Miyagoe-Suzuki and Shin'ichi Takeda
doi:10.1038/nm.3019
Shin'ichi Takeda and colleagues show that loading of muscle results in nitric oxide creation and its conversion to peroxynitrite. The latter molecule then activates TRPV1 in the muscle, leading to increased cytoplasmic concentrations of calcium and activation of mTOR and, thus, muscle hypertrophy. They could replicate these effects without overload by treating mice with a TRPV1 agonist, suggesting a possible therapy for muscle wasting.
| | Technical Report | Top | | | | Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus pp107 - 112
Sapna Devi, Anqi Li, Clare L V Westhorpe, Camden Y Lo, Latasha D Abeynaike, Sarah L Snelgrove, Pam Hall, Joshua D Ooi, Christopher G Sobey, A Richard Kitching and Michael J Hickey
doi:10.1038/nm.3024
The glomerulus, unlike many capillary beds, readily supports leukocyte recruitment, but little is known about the actions of leukocytes upon recruitment to glomeruli. Devi and colleagues have addressed this issue with a multiphoton, confocal microscopy-based approach to shed light on glomerular inflammation. Induction of inflammation in mice did not increase the number of leukocytes recruited to glomeruli but prolonged the duration of leukocyte retention and migration.
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