Articles in 2008

Early identification of individuals with colorectal cancer who are at high risk of metastasis might help guide treatment choice and improve outcome. Stein et al. now report that MACC1, a previously undescribed gene, is a prognostic indicator of colorectal cancer and describe its role as a transcriptional regulator of MET, which encodes the hepatocyte growth factor receptor and promotes metastasis of a variety of cancers.

Aberrant neuronal migration during development leads to defects in cortical development and to an increased seizure susceptibility. Now, Joseph LoTurco and his colleagues show that it is possible to re-invoke neuronal migration perinatally in rodents and reposition neurons into their correct cortical location (pages 17–18).

Notch signaling has a crucial role in T cell acute lymphoblastic leukemia (T-ALL), but γ-secretase inhibitors (GSIs), which block the Notch pathway, cause intestinal toxicity that limits their use. Adolfo Ferrando and his colleagues now report that glucocorticoids can reverse the gut toxicity of GSIs, and GSIs can restore sensitivity of T-ALL cells to glucocorticoids, suggesting that this combination may have clinical utility in T-ALL and other diseases (pages 20–21).

Children born to mothers with lupus have a higher rate of learning disorders. Now, in mouse studies, Betty Diamond and her colleagues show that neurotoxic antibodies found in mothers with lupus are transferred to the brains of their offspring. This leads to abnormalities in cortical formation during development and in cognitive function when the pups become adults.

A formalin-inactivated vaccine from the 1960s against respiratory syncytial virus (RSV) failed to protect children. Although scientists thought that its failure resulted from formalin disruption of protective antigens, it is now shown that it resulted from low antibody avidity for protective epitopes after poor Toll-like receptor (TLR) stimulation. RSV vaccines could therefore become effective by including TLR agonists in their formulation (pages 21–22).

A goal of cancer research is to develop specific and sensitive tumor-imaging techniques for early detection while minimizing background signals from nontarget, 'normal' tissues. The authors have designed a 'pH-activatable' probe, consisting of a targeted macromolecule (monoclonal antibody) and a fluorescence probe, which is activated after internalization in the lysosomes of targeted cancer cells. The utility of this approach for imaging HER2-positive lung cancer cells in mice is shown.

Mitogen-activated protein (MAP) kinases are known to promote cardiac hypertrophy, but how upstream hypertrophic signals induce these kinases to cause hypertrophy has not been clear. Lorenz et al. now uncover a new mechanism of MAP kinase activation and demonstrate the crucial role that this mechanism has in the hypertrophic response.

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.