Volume 14 Issue 12, December 2008

From his early years as a medical student at Harvard University to his job as the director of the HIV/AIDS unit at the World Health Organization (WHO), Jim Yong Kim has worked toward building health care systems to provide care for poor people on a global scale. In the late 1980s, Kim worked with a team of doctors from the Cambridge, Massachusetts–based nonprofit Partners in Health to upend conventional wisdom on treatment for drug-resistant tuberculosis in the shantytowns of Lima, Peru. The team's campaign brought the price of tuberculosis drugs down about 90%. Kim, a physician who also has a doctorate in medical anthropology, says that the success helped overturn the notion that the disease could not be treated in such a poor setting. While at the WHO, he turned his attention to AIDS. In 2003, amid much skepticism, his team launched the global '3 by 5' campaign, an ambitious movement aimed at providing antiretroviral drugs to 3 million people worldwide by 2005. Today, Kim leads the François-Xavier Bagnoud Center for Health and Human Rights at the Harvard School of Public Health, where he oversees programs to address health issues plaguing poor childrenóespecially those afflicted with AIDS. Kim discussed the current state of universal AIDS treatment and the role of biomedical research in promoting social justice with Prashant Nair.

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).

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).

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).

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.

Glutamate NMDA receptors are involved in pain signaling, but inhibiting them would have too many side effects. These authors show that inhibiting the binding of NMDA receptors to Src, a molecule that is resposible for amplifying glutamate signaling, reduces inflammatory and neuropathic pain in mice and rats (pages 1313–1315).

Retinoic acid and arsenic induce the differentiation of acute promyelocytic leukemia (APL) cells and clinical responses in individuals with APL. Nasr and colleagues now show that by triggering the degradation of the PML-RARA oncogenic fusion protein retinoic acid and arsenic also deplete the leukemia initiating cells, accounting for disease remission in a mouse model of APL.

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).

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).

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.

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.

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).

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.

In HIV research, new types of reagents are needed to target infected cells and overcome HIV's ability to vary its HLA-I-restricted antigens and escape from host cytotoxic T lymphocytes. Here Varela-Rohena and colleagues use phage display technology to generate high-affinity T-cell antigen receptors that recognize common epitope-escape variants of the immunodominant HLA-A^*02-restricted, HIVgag-specific peptide SLYNTVATL (SL9).