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In this issue,Richard Gallo and his colleagues show that commensal bacteria on the skin can dampen inflammation resulting from injury. The cover image shows a colored scanning electron micrograph of the commensal bacteria Staphylococcus epidermidis. Credit: David Scharf/Photo Researchers, Inc.
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.
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.
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.
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.
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.
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).
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).
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.
The deposition of excess scar tissue that occurs in lung fibrosis is known to be mediated by transforming growth factor-β (TGF-β). Prostaglandin F2α and the F prostanoid (FP) receptor are now identified as mediators that act independently of TGF-β (pages 1426–1430).
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.
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.
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.
Gökhan 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.
Contrary to the widely held view that impaired γ-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.
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.
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.
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.
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.
Idiopathic pulmonary fibrosis, or lung scarring, is known, at least in part, to be driven by TGF-β signaling. Shuh Narumiya and colleagues now find that prostaglandin F2α receptor also has a key role in this disease, independently of TGF-β signaling, and that its genetic deletion ameliorates disease progression in a mouse model.
Adverse events stemming from the use of retroviral vectors in humans has prompted the search for methods predicting the fate and biological consequences of gene-modified cells after vector insertion. Methods of integration site analysis, such as linear amplification-mediated PCR (LAM-PCR), rely on use of restriction enzymes and identify only a fraction of all genomic integrants. This report describes a non–restriction enzyme–based LAM-PCR technique that provides comprehensive, unbiased integration site analysis.