Articles in 2012

Gemcitabine and 5-fluorouracil are two commonly used chemotherapeutic agents for the treatment of cancer. François Ghiringhelli and colleagues now report that the antitumor efficacy of these agents is mitigated by myeloid derived suppressor cells (MDSCs). The authors show that these drugs can activate the NLRP3 inflammasome, leading to increased secretion of IL-1β by MDSCs and IL-17 production by CD4⁺ T cells, which can promote tumor growth.

Shin'ichi Takeda and colleagues show that loading of muscle results in nitric oxide creation and its conversion to peroxynitrite. The latter molecule then activates TRPV1 in the muscle, leading to increased cytoplasmic concentrations of calcium and activation of mTOR and, thus, muscle hypertrophy. They could replicate these effects without overload by treating mice with a TRPV1 agonist, suggesting a possible therapy for muscle wasting.

The mechanism whereby activation of G protein–coupled receptors (GPCRs) increase the production of amyloid-β (Aβ) peptide remains unclear. Here Bart De Strooper and colleagues show that the GPCR adaptor protein β-arrestin 2 promotes Aβ production by associating with APH-1A and increasing γ-secretase activity. Overexpression of β-arrestin 2 increases Aβ generation, whereas mice lacking β-arrestin 2 have reduced amyloid accumulation. Moreover, expression of β-arrestin 2 is elevated in individuals with Alzheimer's disease, suggesting a potential therapeutic target aimed at reducing amyloid production.

Defects in mitochondrial function have been believed to contribute to insulin resistance. Myung-Shik Lee and colleagues now show that mitochondrial dysfunction in muscle induced by tissue-specific deficiency of autophagy results in upregulation of Fgf21 and improved metabolism, suggesting that at least some mitochondrial dysfunction may actually be beneficial.

Oncolytic virotherapy has been tested in cancer patients, but its efficacy is uncertain. Alvarez-Breckenridge et al. now report that in mouse models of glioblastoma, an antiviral response mediated by natural killer (NK) cells may impair the anticancer efficacy of oncolytic virotherapy. Their findings suggest that limiting the cytolytic activity of NK cells might enhance replication of oncolytic viruses and increase tumor cell killing.

Proinflammatory cytokine expression increases as a result of amyloid deposition in Alzheimer's disease. Frank L. Heppner and colleagues show that genetic and pharmacological inhibition of IL-12 and IL-23 signaling reduces plaque load and improves cognitive deficits in mouse models of Alzheimer's disease. As the concentration of p40 is also increased in the cerebrospinal fluid of individuals with Alzheimer's disease, this suggests that this pathway may be targeted therapeutically in patients.

The peptidase DPP4 has a wide variety of target proteins, including the chemokine SDF-1 and the hormone GLP-1. Hal Broxmeyer and his coworkers now identify colony-stimulating factors as a new class of DPP4 substrates, including GM-CSF, G-CSF, IL-3 and erythropoietin. Treatment of mice with a clinically approved, orally available DPP4 inhibitor improved hematopoietic recovery after radiation or chemotherapeutic drug administration, pointing to potential clinical applications of these findings.

Currently there is no single imaging system that can offer adequate spatial and temporal resolution to accurately assess many of the important factors involved in peripheral arterial diseases. Here, an epifluorescence imaging approach is offered that overcomes many of the current limitations and uses the near-infrared fluorescence of single-walled carbon nanotubes as fluorophores in the second near-infrared window (beyond 1,000 nm). Its use is demonstrated for imaging blood vessels in mouse hindlimb vasculatures millimeters deep in vivo.

Axonal and neuronal damage are commonly seen in patients with multiple sclerosis. Manuel A. Friese and his colleagues now report that the cation channel transient receptor potential melastatin 4 (TRPM4) is upregulated in multiple sclerosis lesions in patients and contributes to disease in vivo. Genetic deletion or pharmacological inhibition of TRPM4 in a mouse model of multiple sclerosis reduces clinical scores and is neuroprotective, suggesting this may represent a novel therapeutic target.

Hydrocephalus is a neurological disorder characterized by expansion of the ventricles. In a mouse model, the authors identified a role for neural progenitors and for platelet-derived growth factor signaling in the pathogenesis of neonatal hydrocephalus. Targeting this pathway reduced ventricular volume, pointing to a new therapeutic target for this condition.

A molecular mechanism in the brain and individual tissues allows mammals to adapt to a 24-hour clock. Garret FitzGerald and colleagues now show that genetic deletion of one member of this pathway specifically in the fat of mice results in acutely altered lipid profiles that, in turn, result in increased feeding and obesity. This could explain why human night-shift workers are at an increased risk for obesity and metabolic disease.

Estrogen is beneficial for obesity and type 2 diabetes, though its use is limited by important side effects. In a new study, Matthias Tschöp and colleagues avoid this issue by chemically linking estrogen to the hormone GLP-1 to selectively target metabolically relevant tissue and show that the conjugated compound corrects obesity, hyperglycemia and dyslipidemia in mice. This approach could be used for other hormone pairs to treat other diseases.

Attenuated viruses can be highly effective vaccines. In this issue, Ralph Baric and colleagues report that inactivating mutations in the exonuclease ExoN of a mouse-adapted SARS coronavirus impair replication fidelity and cause a mutator phenotype. The resulting attenuated virus protected mice against a lethal coronavirus challenge.

Hematopoietic stem cells are difficult to maintain in vitro, hampering their clinical use. Jian Huang et al. show that mouse and human hematopoietic stem cells can be maintained in culture in the absence of exogenous cytokines by combined treatment with agents that activate Wnt and inhibit mTOR signaling, two major signaling pathways implicated in stem cell homeostasis. Moreover, treatment with two such compounds used clinically increases the number of hematopoietic stem cells in mice in vivo.

Cancer cells shed large numbers of small, membrane-bound microvesicles (MVs) into the circulation, which have diagnostic potential but have proved difficult to analyze in a point-of-care setting. Huilin Shao and colleagues have developed a microfluidic chip with an integrated NMR detection system for the rapid profiling of circulating MVs directly from blood samples of patients with glioblastoma. The system was used to distinguish cancer cell–derived MVs from host cell–derived MVs and to measure treatment effects in vivo.