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).

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).

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.

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).

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).

Niemann-Pick type C1 is a lysosomal storage disease caused by mutations in the NPC1 gene. The authors show that NPC1 regulates calcium levels in the lysosome, and calcium dysregulation could be the proximal event in inducing the accumulation of lipids that characterizes the disease.

Although major histocompatibility complex (MHC) class II alleles and CD4⁺ T cells have been implicated in multiple sclerosis, Friese et al. provide here the first direct evidence incriminating MHC class I genes and CD8⁺ T cells in the pathogenesis of this autoimmune disorder (pages 1150–1151).

Bjorn Olsen and his coworkers shed light on the molecular mechanisms underpinning the proangiogenic properties of endothelial cells in hemangiomas, tracing these properties to decreased activity of a signaling pathway involving NFAT transcription factor regulation of VEGFR1 receptor expression. They also identify germline mutations in genes encoding elements of this signaling pathway in a subset of individuals with hemangioma and suggest that interventions in this pathway could have therapeutic effects (pages 1147–1148).

Pauci-immune crescentic glomerulonephritis—an inflammatory disease of the kidneys— may be triggered by bacterial infection. Kain et al. show that almost all individuals with this disease have auto-antibodies to the membrane protein LAMP-2. These antibodies cross-react with the bacterial adhesion FimH, and immunization with FimH causes disease in rats.

The mechanisms that control blood vessel formation are incompletely understood. Sylvain Chemtob and his colleagues now find that blood vessel formation in mouse and rat retinas is controlled by succinate generated during hypoxic and ischemic conditions. Succinate acting through its receptor, GPR91, on retinal ganglion neurons, triggers secretion of canonical proangiogenic factors and the formation of new blood vessels to reinstate adequate tissue supply. This work also identifies GPR91 as a potential therapeutic target for the treatment of ischemic retinopathies.

Although increased levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) have been associated with cardiac disease, whether this enzyme has a causal role in the development of atherosclerosis has not been clear. Wilensky et al. now show in a pig model of atherosclerosis that a selective Lp-PLA2 inhibitor reduces progression to complex atherosclerotic lesion formation, an effect that is associated with decreased infiltration of inflammatory cells into the lesions. These results support the use of Lp-PLA2 inhibitors for the treatment of atherosclerotic cardiovascular disease.

Mitochondrial dysfunction has been described in Alzheimer's disease, but how it is induced has remained unclear. Shi Du Yan and her colleagues find that a neurotoxic amyloid protein associated with the disease binds a mitochondrial protein called cyclophilin D and causes neuron death. The authors show that Alzheimer's disease model mice that lack cyclophilin D show improvements in learning and memory.

Unlike HIV-infected humans or SIV-infected rhesus macaques, natural monkey hosts for SIV do not show immune activation or progress to AIDS, even though they have high viral loads after infection. Differences in the innate immune response in these monkeys may provide a clue as to why they remain healthy.

Currently, there are few options for treating chronic kidney disease. The immunosuppressant cyclosporine A is effective, but the mechanism has been unclear. In this new report, the authors now show that the benefit of cyclosporine A is not through an effect on the immune system but rather through stabilizing the cytoskeleton, and thus the integrity, of a key cell type needed for proper kidney function.

Resistance to drugs is a clinical problem. Downregulating the gene RPN2, which encodes part of an N-oligosaccharyl transferase complex, sensitized breast cancer cells to the cancer drug docetaxel in vivo and in vitro. RPN2 might be a therapeutic target against drug resistance in cancer.