Volume 16 Issue 6, June 2010

The CTSA program has sped up the pace of research by promoting shared informatics tools, such as the four featured here. Not all of these tools are funded fully by the CTSA—but the program has enabled individual institutions to support these projects and fostered their dissemination.

Induced pluripotent stem (iPS) cells are just beginning to shed new light on disease biology. From day one of this burgeoning area of study, stem cell pioneer George Daley of Children's Hospital in Boston has remained involved in this fast-paced field. Ahead of the June annual meeting of the International Society for Stem Cell Research (ISSCR) in San Francisco, Elie Dolgin spoke to Daley about when and how reprogrammed stem cells will deliver.

Each cell in the body possesses hundreds to thousands of mitochondria, known as 'powerhouses' for the energy they provide. But gene mutations can cause these important organelles to fail, often resulting in devastating disease. Erica Westly reports on the patient advocates—and politicians—pushing for new treatments for mitochondrial disease.

The notoriously drug-resistant bug MRSA has made headlines for years, but a whole other class of bacteria may prove even more troublesome. These microbes, Gram-negative bacteria, are increasingly a threat—and yet not a single late-stage drug in development specifically targets them. Christian Torres follows one man's quest to get the antibacterial pipeline flowing once again.

Cancer clinical trials in the US are at a major crossroads. Current government-sponsored research is some of the best in the world, but the field shares a worrying number of similarities with the American auto industry in its heyday. For clinical research to survive, the field must transform itself now to prevent a similar decline.

Basophils have recently been identified as antigen-presenting cells that are required for optimal antibody responses. New findings now show that activation of these cells can amplify autoimmune responses in systemic lupus erythematosus (SLE) (pages 701–707).

Cytokines have a fundamental role in orchestrating innate immune responses to bacterial infections. Interleukin-33 (IL-33) is now shown to protect from sepsis by promoting neutrophil influx into the focus of infection (pages 708–712).

Activation of Toll-like receptor (TLR) signaling by microbes in the intestine promotes tumor growth in genetically susceptible mice. Inactivation of extracellular signal–regulated kinase (ERK), a molecule downstream of TLR signaling, may offer a route to preventing colorectal cancer (pages 665–670).

There is no cure for osteoarthritis—the most common disease of the joints. By piecing together the molecular events that drive the progression of this debilitating disease, recent studies published in Nature Medicine put hypoxia-inducible factor-2α (HIF-2α) in the driver's seat, opening up new avenues for early detection and treatment (pages 678–686 and 687–693).

Numerous factors can contribute to sudden cardiac death, from underlying disease after myocardial infarction to genetic variants that can claim young lives. In 'Bedside to Bench', Stanley Nattel examines recent clinical studies suggesting that a particular type of readout on an electrocardiogram (ECG) may increase the risk of the condition. This ECG 'variant' is relatively common and was previously thought to be benign. In 'Bench to Bedside', Gordon Tomaselli and Andreas Barth take a look at studies at the bench examining how oxidative stress may promote sudden cardiac death.

Adeno-associated virus serotype 6–mediated transduction requires the epidermal growth factor receptor.

This study dissects the contribution of TLR signaling to intestinal tumorigenesis. MyD88 signaling, known to be required for tumorigenesis in Apc^min/+ mice, is shown to be triggered by ligands from the microflora. MyD88-mediated activation of the MEK-ERK cascade stabilizes c-Myc by preventing its ubiquitin-mediated degradation. The findings link oncogenic c-Myc function to immune signaling and uncover MEK inhibition as a new therapeutic strategy to treat intestinal tumors.

The transcription factor ATF5 is associated with malignancy in glioblastomas. In this report, the authors devise a unique shRNA screen to identify and characterize the upstream regulators and downstream effectors of ATF5 in brain tumors. ATF5 upregulation is mediated by a concomitant increase in FRS2, PAK1 and CREB3L2 and promotes survival by elevating Mcl1 expression. This pathway represents a novel therapeutic target validated by the antitumor efficiency of the Raf kinase inhibitor sorafenib.

In two studies from teams led by Hiroshi Kawaguchi and Jang-Soo Chun, a role for HIF-2α in osteoarthritis has been uncovered. Along with identifying the molecular mechanism, the teams found that HIF-2α expression is increased in human osteoarthritic tissue, and mice deficient for the protein are protected in two osteoarthritis models, suggesting that HIF-2α could be a therapeutic target.

In two studies from teams led by Hiroshi Kawaguchi and Jang-Soo Chun, a role for HIF-2α in osteoarthritis has been uncovered. Along with identifying the molecular mechanism, the teams found that HIF-2α expression is increased in human osteoarthritic tissue, and mice deficient for the protein are protected in two osteoarthritis models, suggesting that HIF-2A could be a therapeutic target.

Spinal cord injury leads to flaccid paralysis resulting from the loss of descending serotonergic modulation. Murray et al. demonstrate that spontaneous recovery of motoneuron excitability is associated with alternative mRNA editing and increased expression of constitutively active 5HT_2C serotonin receptors. Activation of these receptors leads to large persistent calcium currents, sustained muscle contractions and restoration of locomotion. However, in the absence of descending modulation from the brain, this leads to spasticity. Inhibiting constitutive 5-HT receptor activity is effective in reducing spasticity in rats and humans following spinal cord injury.

Basophils initiate T helper type 2 responses after exposure to allergens and IgE immune complexes. Juan Rivera and his colleagues find that elevated amounts of IgE in Lyn^−/− mice drive basophil activation, secretion of T helper type 2 cytokines and production of autoantibodies, leading to a lupus-like phenotype in mice and to glomerulonephritis. Depletion of basophils or deficiencies in IgE or interleukin-4 are sufficient to reduce autoantibody production and prevent kidney damage. Data from subjects with SLE suggest that increased IgE levels and activated basophils may contribute to disease.

The treatment options for sepsis are limited in scope and efficacy, resulting in frequent human fatalities. Liew and colleagues now report that interleukin-33 is a promising therapeutic strategy that increases neutrophil recruitment to the site of infection and bacterial clearance and decreases mortality in a mouse model of sepsis.

In a mouse model of systemic autoimmunity, the damage-associated molecular pattern molecules Mrp8 and Mrp14 are essential for the induction of autoreactive CD8⁺ T cells and for disease development in a TLR4– and IL-17–dependent manner. A similar mechanism might be at play in people with cutaneous lupus erythematosus.

Fan et al. present a method to dissect the cellular immune response to transplanted tissue by tracking various T cell populations in both the circulatory compartment by in vivo flow cytometry and at the graft site by endoscopic confocal microscopy. The allograft response was followed for two weeks in a mouse model in which pancreatic islet transplants were placed beneath the renal capsule. This approach may help to develop treatment options that improve transplantation outcomes.