Articles in 2008

Granulysin, a powerful cytolytic protein secreted from immune cells, underlies an extreme and deadly response to common medications, in which the skin blisters and sloughs off. The findings may also have implications for bone marrow transplant recipients suffering from graft-versus-host disease (pages 1343–1350).

Interfering with the adhesion of immune cells to the cerebral vasculature holds seizures in check, potentially opening a new realm of therapeutics (pages 1377–1383).

A small peptide eases pain in several types of mouse models. The peptide targets a protein interaction within a pain-mediating complex—containing the N-methyl-D-aspartate receptor—without affecting normal physiological processes (pages 1325–1332).

The phosphoinositide 3-kinase (PI3K) and RAS oncoproteins are activated in many major tumor types and control linked signaling pathways. An inhibitor of PI3K is now shown to shrink tumors in transgenic mouse cancer models. The drug also blocks RAS-induced lung tumors when combined with an inhibitor of mitogen-activated protein kinase kinase (pages 1351–1356).

The recent proposal from the European Commission (EC) for a new directive on the protection of animals used in research is well intentioned, but some of its ramifications could cause it to backfire.

Toll-like receptors (TLRs), molecules that recognize molecular components of microbes, have taken center stage in immunologists' view of how innate immunity is triggered. A study in people genetically deficient for MyD88, a molecule central to TLR signaling in mice, should now spur a reexamination of simple views of TLR biology, as Rino Rappuoli and his colleagues explain. Delphine J. Lee and Robert L. Modlin examine how TLR9 recognition of self DNA, instead of microbe DNA, may prompt autoimmunity.

Inhibitors of PI3 kinase are in development for the treatment of cancer. But whether these compounds will work as single agents remains to be seen. Engelman et al. now show that a PI3K-mTOR inhibitor is effective in a mouse model of lung cancer induced by a mutant PIK3CA but has no effect on Kras-induced tumors. Combining the PI3K-mTOR inhibitor with a MEK inhibitor induced regression of mouse Kras tumors, suggesting that such combinations may be beneficial in human tumors (pages 1315–1316).

Ectopic ossification often involves the transformation of soft tissue into bone. In this new study, Paul Yu et al. show that inflammation is a key step in disease progression and that a small molecule inhibitor of the disease gene’s protein product is therapeutic, thus offering a potential treatment for this devastating condition.

Inhibition of mineralcorticoid receptor activity is known to improve the outcome of chronic kidney disease. In this new report, Toshiro Fujita and his colleagues show that Rac1 strongly potentiates mineralcorticoid receptor signaling by enhancing its nuclear localization and that Rac1 inhibition is ameliorative in two rodent models of renal disease.

When viruses infect cells, they trigger changes such as exposure of phosphatidylserine on the cell surface. Thorpe et al. have shown that this 'inside-out' phosphatidylserine can be targeted by an antibody, and this approach can clear virus infection in mice.

Peter Eirew and his colleagues describe a new assay for detecting, quantifying and characterizing normal human mammary epithelial stem cells. The assay, which combines in vivo transplantation under the kidney capsule of immunodeficient mice and an in vitro colony-forming assay, provides a system for studying the mechanisms regulating normal human mammary stem cell proliferation and differentiation in vivo and in human breast cancer.

The authors examine how brain inflammation affects the development of epilepsy. They show that genetic or antibody-mediated blockade of leukocyte-vascular interactions reduces epileptogenesis in mice (pages 1309–1310).

Drug hypersensitivity reactions can result in life-threatening epidermal necrosis caused by cytotoxic T lymphocytes and natural killer cells. Chung et al. show that an unusual form of granulysin secreted from these cells is largely responsible for the cell death (pages 1311–1313).