Research articles

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.

Yousefi et al. reveal a new function of eosinophils and suggest they have an antibacterial role in the gut. The cells fire spurts of mitochondrial DNA and granule proteins in response to infection, entrapping and killing the extracellular bacteria (pages 910–911).

Chaperone-mediated autophagy (CMA), a mechanism for the lysosomal degradation of proteins, declines in aging cells. Using transgenic mice in which such a decline does not occur in the liver, the authors found that preserving CMA leads to reduced accumulation of damaged proteins and improved organ function in aged mice (pages 909–910).

A novel immunization strategy that involves prime-boost vaccination with a recombinant adenovirus-poxvirus vector can induce strong, antigen-specific antibody responses. Antibodies induced by this viral-vector platform against a Plasmodium antigen are effective in vivo and in vitro.

Promising results using cell therapy in animal models of muscular dystrophy have recently been reported. However, a limitation of this previous work is that therapeutic effects have been shown only in young animals, whereas many patients who could benefit from such therapy are at advanced stages of disease. As dystrophic muscle ages, it becomes sclerotic and is infiltrated by fat, presenting an obstacle to cell delivery. This paper reports that this obstacle can be overcome by pretreatment of the muscle with tendon fibroblasts that have been genetically modified to express an angiogenic factor and a metalloprotease.

Direct proof that women with pre-eclampsia develop autoantibodies to the AT₁ receptor, which explains the hypertension and other symptoms of the disease, is now provided. Additionally, blocking these autoantibodies or treating with losartin, a drug that targets the AT₁ receptor, in a new mouse model of this condition helps ameliorate disease outcome (pages 810–812).

The transcription factor Foxa2, which is key for the hepatic control of glucose metabolism, is now shown in this report to also be crucial for proper bile acid homestasis in the liver, as well as to be misregulated in human cholestatic diseases.

Acidification of the phagosome is a key mechanism thought to be used by macrophages against Mycobacterium tuberculosis. The authors identify a previously undescribed gene that confers acid resistance to the bacterium and is essential for virulence (pages 809–810).

Studies of gene expression in lung cancer have the potential to affect patient care, but the general applicability of the derived classifiers is unclear. David Beer and his colleagues now analyze more than 400 lung tumors from subjects at six institutions using eight different classifiers and show that the combination of molecular and clinical data best predicts patient survival (pages 812–813).

The degree of lymph-node metastasis in prostate cancer is crucial for both staging the disease and planning treatment. Here, Burton and colleagues describe a one-step, non-invasive imaging technology using prostate-specific adenoviral vectors that express imaging reporter genes. This set-up specifically and accurately detects lymph-node metastases in a model of human prostate cancer and eliminates the need for invasive lymphadenectomy required by the current lymphoscintigraphy method.

A major challenge in biomedicine is the rapid and accurate measurement of biomarkers in biological samples. Here, Lee et al. describe a chip-based NMR diagnostic platform that can perform sensitive and selective measurements on small volumes of unprocessed biological samples. This miniaturized biosensing system is high throughput, low cost and portable, and its utility is shown in a number of biomedical applications.

Kuznetsov and his colleagues address a pressing problem in risk assessment for predisposition to breast cancer—whether a particular allele is cancer predisposing or not. Using a two-tiered approach, they have developed a functional assay for the classification of BRCA2 sequence variants of unknown importance. The assay may serve as a model to generate functional assays for other human disease genes.

Statins and aminobisphosphonates inhibit post-translational modifications and membrane accumulation of progerin, the protein that causes Hutchinson-Gilford progeria syndrome, pointing to a potential combination therapy for this disease.

People with the metabolic syndrome often develop gallstones. Why these two disorders are linked has not been not clear, but now Kahn and his colleagues have shown that lack of insulin signaling in the liver leads to dysregulation of genes that control the transport and synthesis of bile acids, thus altering the proper profile of bile salts and resulting in the formation of gallstones.

BACE is an enzyme necessary for the generation of neurotoxic amyloid-β in Alzheimer's disease. Claes Wahlestedt and his colleagues identify a noncoding RNA that is upregulated in the brains of individuals with Alzheimer's disase. This noncoding RNA increases expression of BACE, driving amyloid-β generation and possibly disease progression.

Tuberous sclerosis is a neurological disorder associated with seizures and cognitive dysfunction. Alcino Silva and his colleagues find that rapamycin, an inhibitor of the mTOR signaling pathway, can ameliorate cognitive deficits in a mouse model of the disease.

tPA is a clot-buster used to treat stroke, but if it's given too late after stroke onset, it can cause complications like hemorrhage. Daniel Lawrence and his colleagues show that a US Food and Drug Administration–approved kinase inhibitor, Gleevec, can prevent this side effect, thereby extending tPA's therapeutic window.

The synaptotoxic Aβ protein aggregates in the brains of individuals with Alzheimer's disease. Dennis Selkoe and his colleagues identify the size of the Aβ aggregate in the brains of individuals with Alzheimer's disease that is responsible for the deficits of learning and memory that characterize the disease.

Siliciano and his colleagues propose a new index for measuring the antiviral activity of anti-HIV drugs in vitro, which suggests that there are limitations to the efficacy of antiviral drugs on the basis of their mechanism of action. They suggest that the new index is a more accurate way of measuring antiviral activity and that it correlates well with clinical outcomes.