December 2009 Volume 15 Number 12, pp 1335 - 1436
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NATURE MEDICINE PODCAST
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Missing the mark
We take a look at how researchers are grappling with problems in prostate cancer detection. Plus, Darwin goes to medical school.
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EDITORIAL
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Cutting out the middleman p1335
doi:10.1038/nm1209-1335
Innovation in translational research has often emerged from the biotechnology industry. In a climate in which it is increasingly hard to found a successful company, direct technology transfer from academia to the pharmaceutical industry poses an additional threat to small biotechs.
http://links.ealert.nature.com/ctt?kn=140&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
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NEWS
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Nutt dismissal in Britain highlights diverging drug views p1337
Daniel Cressey
doi:10.1038/nm1209-1337
http://links.ealert.nature.com/ctt?kn=190&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Groups say med school training must evolve p1338
Daniel Cressey
doi:10.1038/nm1209-1338a
http://links.ealert.nature.com/ctt?kn=191&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Industry tightens its purse strings p1338
doi:10.1038/nm1209-1338b
http://links.ealert.nature.com/ctt?kn=196&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Willing subjects live longer but blur clinical trial results p1338
Asher Mullard
doi:10.1038/nm1209-1338c
http://links.ealert.nature.com/ctt?kn=197&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Markers of dispute pp1339 - 1343
Virginia Hughes
doi:10.1038/nm1209-1339
The gold standard for early detection of prostate cancer, PSA, has recently come under fire for its high rate of false positives. Virginia Hughes investigates some of the researchers hunting for better alternatives and asks whether their promises of creating viable-and profitable-biomarker tests will ever be realized.
http://links.ealert.nature.com/ctt?kn=192&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Prostate clues in the genome p1342
Virginia Hughes
doi:10.1038/nm1209-1342
http://links.ealert.nature.com/ctt?kn=195&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
News in brief pp1344 - 1345
doi:10.1038/nm1209-1344
http://links.ealert.nature.com/ctt?kn=188&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Straight talk with...Warwick Anderson pp1346 - 1347
Simon Grose
doi:10.1038/nm1209-1346
In June 2006, Warwick Anderson became chief executive of Australia's National Health and Medical Research Council (NHMRC) as the institution gained new status as a fully independent agency. He talked to Simon Grose about his first three years in the job and the NHMRC's accelerated evolution.
http://links.ealert.nature.com/ctt?kn=189&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
2009 IN REVIEW
Yearbook 2009 p1348
Melinda Wenner
doi:10.1038/nm1209-1348
Behind the news, there are always the newsmakers. Inspired by the high school yearbook tradition, we have rounded up a few such individuals worthy of notice in 2009. Some stepped into the spotlight eagerly, whereas others operated behind the scenes.
http://links.ealert.nature.com/ctt?kn=185&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
2009 IN REVIEW
Notable advances p1349
Melinda Wenner
doi:10.1038/nm1209-1349
Some of the key papers published in 2009
http://links.ealert.nature.com/ctt?kn=186&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
2009 IN REVIEW
Timeline of events ...a brief history of what made news this year p1350
Melinda Wenner
doi:10.1038/nm1209-1350
http://links.ealert.nature.com/ctt?kn=176&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
2009 IN REVIEW
2009 by the numbers pp1351 - 1352
doi:10.1038/nm1209-1351
http://links.ealert.nature.com/ctt?kn=177&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
2009 IN REVIEW
Drugs in the headlines p1353
Victoria Aranda
doi:10.1038/nm1209-1353a
This year witnessed both surprising successes and unexpected failures in basic and clinical drug development. There were also mixed results for some newly tested drugs, which will probably prompt a careful reassessment of their therapeutic value. Our drug watch compilation summarizes the most talked about therapies of the year.
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2009 IN REVIEW
In case you missed it p1353
doi:10.1038/nm1209-1353b
A look at stories that fell under the radar in 2009
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BOOK REVIEW
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Breaking the spell of food p1354
Stephen O'Rahilly reviews The End of Overeating: Taking Control of the Insatiable North American Appetite by David Kessler
doi:10.1038/nm1209-1354
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NEWS AND VIEWS
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Memantine strikes the perfect balance pp1355 - 1356
Albert R La Spada
doi:10.1038/nm1209-1355
Excessive stimulation of glutamate receptors results in excitotoxicity and has a role in a variety of neurodegenerative disorders, including Huntington's disease. By blocking pathological extrasynaptic activity but preserving normal synaptic function, the N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine-at the proper dosage-emerges as a potential treatment for such neurological disorders (pages 1407-1413).
http://links.ealert.nature.com/ctt?kn=181&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Atherosclerosis: keep your macrophages in shape pp1357 - 1358
Xueqing Liu and James M Ntambi
doi:10.1038/nm1209-1357
Lipid accumulation leads to atherosclerosis partly by eliciting lethal levels of cellular stress in macrophages. A signaling pathway that drives such lipid-induced toxicity is now identified. The findings reveal a chaperoning function that might provide the clue needed to rescue this pathogenic effect (pages 1383-1391).
http://links.ealert.nature.com/ctt?kn=182&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Quelling cholesterol pathway fends off brain damage pp1358 - 1359
Maria T Bengoechea-Alonso and Johan Ericsson
doi:10.1038/nm1209-1358
A molecular pathway known for regulating cholesterol and lipid metabolism is now implicated in stroke (pages 1399-1406). The pathway is bumped up by N-methyl-D-aspartate glutamate receptors (NMDARs), which are hyperactivated in stroke and other conditions.
http://links.ealert.nature.com/ctt?kn=173&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Beyond TGF-beta: a prostaglandin promotes fibrosis pp1360 - 1361
Mitchell A Olman
doi:10.1038/nm1209-1360
The deposition of excess scar tissue that occurs in lung fibrosis is known to be mediated by transforming growth factor-beta (TGF-beta). Prostaglandin F2alpha and the F prostanoid (FP) receptor are now identified as mediators that act independently of TGF-beta (pages 1426-1430).
http://links.ealert.nature.com/ctt?kn=174&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
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COMMUNITY CORNER
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Milk protein fends off sepsis in premature babies p1362
doi:10.1038/nm1209-1362
http://links.ealert.nature.com/ctt?kn=175&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
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BETWEEN BEDSIDE AND BENCH
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Immune modulation
There are many ways to modulate the immune response in a therapeutic setting. Drugs that target the proinflammatory mediator IL-1, for instance, can counteract disease in certain types of inflammatory conditions. But such drugs do not work well for other conditions, such as rheumatoid arthritis and other autoimmune diseases. New clinical studies, examined by Kingston Mills and Aisling Dunne, provide insight into this discrepancy. Another approach that has worked well in mice harnesses the ability of regulatory T cells to dampen the immune response. But one barrier in the way of successful application to people is the ability of such cells to change their character for the worse. Massimo Gadina and John O'Shea take a look at a basic research study that highlights this dilemma and examine what it means for the future of human trials.
Immune modulation: IL-1, master mediator or initiator of inflammation pp1363 - 1364
Kingston H G Mills and Aisling Dunne
doi:10.1038/nm1209-1363
http://links.ealert.nature.com/ctt?kn=81&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Immune modulation: Turncoat regulatory T cells p1365
Massimo Gadina and John J O'Shea
doi:10.1038/nm1209-1365
http://links.ealert.nature.com/ctt?kn=89&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
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RESEARCH HIGHLIGHTS
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Research Highlights pp1366 - 1367
doi:10.1038/nm1209-1366
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ARTICLES
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A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas pp1369 - 1376
Leandro C Cerchietti et al.
doi:10.1038/nm.2059
By taking advantage of the direct interaction between heat shock protein 90 (Hsp90) and the transcriptional repressor Bcl-6, a purine-derived inhibitor of Hsp90 selectively kills diffuse large B cell lymphomas that depend on the expression of Bcl-6 for their survival.
Abstract: http://links.ealert.nature.com/ctt?kn=91&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=92&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury pp1377 - 1382
Yuping Lai et al.
doi:10.1038/nm.2062
Gallo and his colleagues report that commensal bacteria on the skin help to dampen inflammation caused by skin injury in mice. They show that, after wounding, necrotic cells release RNA that triggers TLR3 on keratinocytes, causing inflammatory cytokine release. Commensal bacteria in the skin suppress this inflammatory response through triggering TLR2 on the keratinocytes.
Abstract: http://links.ealert.nature.com/ctt?kn=82&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=83&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis pp1383 - 1391
Ebru Erbay et al.
doi:10.1038/nm.2067
Gokhan Hotamisligil and his colleagues report that reducing endoplasmic reticulum stress in macrophages by targeting the lipid chaperone aP2 ameliorates atherosclerosis in a mouse model, paving the way for a possible new clinical therapy.
Abstract: http://links.ealert.nature.com/ctt?kn=85&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=87&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Enhanced tonic GABAA inhibition in typical absence epilepsy pp1392 - 1398
David W Cope et al.
doi:10.1038/nm.2058
Contrary to the widely held view that impaired gamma-aminobutyric acid (GABA)-mediated neurotransmission underlies epileptic activity, extrasynaptic GABA-dependent thalamocortical inhibition caused by reduced GABA uptake is reported to be increased in diverse models of absence seizures.
Abstract: http://links.ealert.nature.com/ctt?kn=76&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=61&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries pp1399 - 1406
Changiz Taghibiglou et al.
doi:10.1038/nm.2064
Excitotoxicity mediated by over activation of glutamate receptors results in neuronal loss after ischemia. Activation of sterol regulatory element-binding protein-1 is now shown to be crucial for glutamate-mediated excitotoxic neuronal death in a mouse model of stroke.
Abstract: http://links.ealert.nature.com/ctt?kn=62&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=71&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin pp1407 - 1413
Shu-ichi Okamoto et al.
doi:10.1038/nm.2056
In a mouse model of Huntington's disease, synaptic activation of NMDA receptors induces the formation of huntingtin-containing inclusions, rendering neurons more resistant to death in vivo and in vitro. In contrast, stimulation of extrasynaptic NMDA receptors increases neuronal vulnerability by preventing inclusion formation.
Abstract: http://links.ealert.nature.com/ctt?kn=72&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=69&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Synovial fibroblasts spread rheumatoid arthritis to unaffected joints pp1414 - 1420
Stephanie Lefevre et al.
doi:10.1038/nm.2050
Rheumatoid arthritis usually begins in one joint but spreads to other joints as the disease progresses. Elena Neumann and her colleagues show that rheumatoid arthritis synovial fibroblasts (RASFs) may be key mediators of this process. They show, using a SCID mouse model, that human RASFs can migrate long distances through the bloodstream from diseased cartilage to unaffected cartilage, where they can mount a new attack.
Abstract: http://links.ealert.nature.com/ctt?kn=70&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=67&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
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LETTERS
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Modulating hedgehog signaling can attenuate the severity of osteoarthritis pp1421 - 1425
Alvin C Lin et al.
doi:10.1038/nm.2055
In a new report, Benjamin Alman and his colleagues find that the morphogenic pathway activated by Hedgehog signaling is a key mediator of osteoarthritis, a condition that is marked by irreversible degeneration of the joints and with no current treatment. They also found that blockade of Hedgehog signaling prevented osteoarthritis in a mouse model, suggesting this pathway as a possible target to treat this devastating disease.
Abstract: http://links.ealert.nature.com/ctt?kn=68&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=65&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Prostaglandin F2alpha receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta pp1426 - 1430
Toru Oga et al.
doi:10.1038/nm.2066
Idiopathic pulmonary fibrosis, or lung scarring, is known, at least in part, to be driven by TGF-beta signaling. Shuh Narumiya and colleagues now find that prostaglandin F2alpha receptor also has a key role in this disease, independently of TGF-beta signaling, and that its genetic deletion ameliorates disease progression in a mouse model.
Abstract: http://links.ealert.nature.com/ctt?kn=66&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=136&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
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TECHNICAL REPORT
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Comprehensive genomic access to vector integration in clinical gene therapy pp1431 - 1436
Richard Gabriel et al.
doi:10.1038/nm.2057
Abstract: http://links.ealert.nature.com/ctt?kn=135&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=134&m=34466094&r=MTc2NTQyNDEzOQS2&b=2&j=NjE5MzA0NDYS1&mt=1&rt=0
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Nature Reprint Collection
Immuno-epigenetics
Epigenetic mechanisms are increasingly appreciated to have an important role in immune cell functional diversity and adaptability, and understanding these mechanisms holds considerable potential for revealing new opportunities to therapeutically modulate the immune response in a range of diseases.
This special Collection brings together articles from Nature, Nature Immunology, Nature Reviews Immunology and Nature Reviews Drug Discovery that have contributed to advances and discussions in the field of immune cell epigenetics.
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