Research articles

TNF-α suppresses regulatory T (T_reg) cell function, however the mechanism remains unclear. Here Jingwu Z Zhang and colleagues find that in activated T cells, phosphorylation of FOXP3 promotes its transcriptional activity. TNF-α induces protein phosphatase 1 expression, leading to dephosphorylation of FOXP3 and inhibition of T_reg cell function. In individuals with rheumatoid arthritis, TNF-α–specific antibody treatment restores T_reg cell activity and FOXP3 phosphorylation, suggesting that post-translational modifications, including phosphorylation, regulate FOXP3 activity and T_reg cell–mediated suppression.

Oncolytic viruses are under development for tumor treatment. David Kirn and colleagues now report their results of a randomized phase 2 dose-finding trial of JX-594, an oncolytic immunotherapeutic vaccinia virus, in patients with advanced hepatocellular carcinoma. The study shows that high-dose JX-594 was associated with significantly improved overall survival and induced radiographic responses and antitumor immunity.

Alan Saltiel and his colleagues report that the approved drug amlexanox, currently used to treat asthma and canker sores, is a relatively specific inhibitor of the noncanonical IκB kinases IKK-ɛ and TANK-binding kinase 1 (TBK1) and that it improves metabolic disease in mouse genetic and dietary models of obesity. These results suggest this drug may be repurposed to treat obesity and insulin resistance.

Stefan Kiechl and colleagues show that blockade of receptor activator of nuclear factor-κB (RANKL) signaling in hepatocytes by cell type–specific genetic deletion of its receptor promotes greater insulin sensitivity in both a genetic and a nutritional model of type 2 diabetes. They also show epidemiological evidence that elevated serum concentrations of soluble RANKL are a risk factor for the development of this disease.

Staphylococcus aureus is an important causative agent of many skin infections and produces numerous toxic phenol-soluble modulins that mediate its virulence. Michael Otto and colleagues have now identified the S. aureus genes that encode the peptide transporter responsible for the export of these toxins from the bacteria and reveal its crucial role in abscess formation in the skin.

Usher syndrome is a congenital form of deafness and vestibular dysfunction characterized by mutations in the USH1C gene encoding harmonin. Michelle L. Hastings and her colleagues show in a mouse model of Usher syndrome that early treatment with antisense oligonucleotides corrects defective pre-mRNA splicing of mutant USH1C, increasing full-length harmonin expression and restoring low-frequency hearing and vestibular function.

Mutations in the cytosolic 5′-nucleotidase II gene accelerate the inactivation of chemotherapeutic nucleoside analogs in acute lymphoblastic leukemia (ALL)-promoting lymphoblasts. Increased nucleotide metabolism may therefore constitute an important resistance mechanism in chemotherapy-resilient ALL.

John Chute and his colleagues show that the cytokine EGF protects mouse bone marrow hematopoietic stem cells from radiation injury. EGF signaling in these cells inhibited cell death through repression of the proapoptotic protein PUMA. EGF administration rescued mice from death after total-body irradiation, suggesting a new therapeutic strategy for radioprotection.

Human epididymis protein 4 (HE4), a putative serine protease inhibitor, is upregulated in human and mouse fibrotic kidneys. Inhibiting HE4 inhibited fibrosis in three different mouse models of renal disease, suggesting that HE4 is a new therapeutic target.

Michalina Gora and her colleagues have developed a tethered capsule endoscope in the form of a swallowable pill that does not require sedation and is the size of a one-cent coin. Once swallowed, the device was well tolerated and used to capture three-dimensional microstructural images of the digestive tract, particularly the esophagus, using optical frequency domain imaging. Feasibility was demonstrated in patients with Barrett’s esophagus, including high-grade dysplasia.

The Notch signaling pathway has a key role in shaping the developing heart. Guillermo Luxán et al. identify two human mutations in the gene encoding the Notch pathway protein MIB1 that cause a type of cardiomyopathy, left ventricular noncompaction. The authors show that mice lacking Mib1 in the myocardium have a similar type of cardiomyopathy and analyze how MIB1 deficiency leads to defective ventricular development.

Much of the current understanding of oxygen transport at the capillary level comes from mathematical models. Building on earlier work, Alexandre Parpaleix and his colleagues use two-photon phosphorescence lifetime microscopy to show how brain activity can be noninvasively imaged from measurements of oxygen dynamics in capillaries. They demonstrate the presence of an oxygen partial pressure (PO₂) initial dip at the level of capillaries and show that tissue PO₂ can be inferred from erythrocyte-associated transient values.

Inhibition of prosurvival proteins of the BCL family is a promising anticancer strategy; however, the similarities between the family members make the development of specific agents difficult. Current compounds have been designed to target BCL-2, which is frequently elevated in tumors and is an important prosurvival factor, but also inhibit BCL-X_L, which is required for the survival of platelets; thus, thrombocytopenia is a limiting toxic effect in patients. The authors have engineered anti-BCL drugs to generate a more BCL-2–specific compound that has less affinity for BCL-X_L and, therefore, reduced platelet toxicity. The compound is effective in several tumor models in vivo and had reduced toxicity in three patients with refractory leukemia, showing a promising activity and safety profile to refine and improve proapoptotic therapy in cancer.

TRIP-Br2–null mice are resistant to obesity and insulin resistance and have higher energy expenditure because of increased thermogenesis and oxidative metabolism. As expression of this transcriptional regulator is elevated in fat from obese humans, TRIP-Br2 might be a new therapeutic target against insulin resistance and hyperlipidemia.

RNA editing provides epigenetic diversity and is thought to be decreased in cancer. However, this report describes a phenomenon of increased RNA editing associated with malignancy in human liver tumors. The increased editing of AZIN1 is facilitated by the correlative increase in the editing enzyme ADAR1 and induces an amino acid change that leads to subcellular relocalization, increased stability and affinity for antizyme. This effect impairs antizyme's function and increases the stability of its target oncoproteins, providing protumorigenic functions. The hyperediting of AZIN1 is a protumorigenic event in liver cancer pathogenesis.