Research articles

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.

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).

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.

Mesenchymal stem cells have therapeutic effects in various different models of disease, but how they work is not always clear. Eva Mezey and her colleagues now propose that such cells may prove beneficial in sepsis—and they work by reprogramming innate immune cells (pages 18–20).

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).

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).

The promise of engineered T cells for treating cancer has been mitigated by their poor persistence when transferred to patients. Pule et al. now show that dual-specific T cells that recognize an Epstein-Barr virus (EBV) antigen and a tumor antigen survive longer in individuals with neuroblastoma. Engineering virus-specific T cells to recognize tumor antigens may improve the efficacy of this immunotherapy in latently infected cancer patients (pages 1148–1150).

siRNA is used to silence expression of a specific gene and, if modified by a triphosphate at the 5′ end, will also activate the helicase Rig-I, leading to interferon production. Poeck et al. now combine both of these activities in a single siRNA to kill melanoma cells by crippling a crucial tumor cell survival pathway and triggering an interferon-dependent antitumor immune response (pages 1152–1153).