News & Views in 2011

The nuclear factor-κB (NF-κB) family of regulators is well known for mediating dendritic cell (DC) maturation—that is, the acquisition of the functions required for full activation of T cells. Paradoxically, a key member of this family, NF-κB1, is now also implicated in maintaining DCs in an immature state (pages 1663–1667).

IgA regulates intestinal homeostasis by maintaining appropriate communities of bacteria within the gut. A new study shows that intestinal bacteria regulate metabolism via IgA (pages 1585–1593).

Although protein-polysaccharide conjugate vaccines provide notable clinical benefits, it is still not fully understood how they work. A new mechanism of action for these vaccines has been identified in which T cells can recognize sugar epitopes in the context of the major histocompatibility complex (MHC) provided they are bound to a protein 'anchor', which allows binding of the sugar epitope to the MHC (pages 1602–1609).

Cellular production of nitric oxide (NO) by nitric oxide synthase (NOS) in the face of limiting pools of arginine requires the intracellular citrulline-to-NO pathway, catalyzed by the enzyme argininosuccinate lyase (ASL). People with the urea cycle disorder argininosuccinic aciduria, caused by a deficiency of ASL, have systemic NO deficiency, which can be rescued by the use of an alternative, NOS-independent, nitrite-to-NO pathway.

miR-200 family expression results in highly proliferative ovarian cancer cells. Yet this expression is also linked to longer overall survival in women with ovarian cancer. A new study sheds light into this apparent paradox showing that two members of this family—miR-141 and miR-200a—not only boost tumor growth but also sensitize tumor cells to chemotherapy (pages 1627–1635).

The discovery that skin cells from an adult human can be reprogrammed back to their embryonic stage and then differentiated to produce neuron-like cells in culture opens an opportunity to study disease pathogenesis and screen potential therapeutic drugs. A new study provides an example of this approach for the neuropsychiatric disorder Timothy syndrome (pages 1657–1662).

A new study suggests that regulation of the serum- and glucocorticoid-regulated kinase (SGK1) is important for ensuring uterine receptivity and maintenance of pregnancy (pages 1509–1513). Additional work will be required to determine whether SGK1 could be potentially targeted to treat infertility and prevent miscarriage and whether it can be used as a biomarker.

Although erythropoietin (Epo) is commonly used as a therapy for anemia, recent studies have suggested that Epo therapy is associated with adverse outcomes. A new study shows that polymeric IgA1 positively regulates erythropoiesis through binding to transferrin receptor 1 (Tfr1), suggesting new therapeutic routes for anemia (pages 1456–1465).

The identification of a new mode of cell-cell communication mediated by semaphorin 4D (Sema4D) and Plexin-B1 has added another level to the regulatory balance between bone formation and resorption (pages 1473–1480). This study also highlights Sema4D as a potential target for the development of new therapeutics for osteoporosis and other bone disorders associated with increased resorption.

Increasing rates of obesity and obesity-associated type 2 diabetes are threatening to reverse recent gains in reducing the rates of cardiovascular and thrombotic disease. A new study in obese mice shows that tissue factor, the principal initiator of coagulation, is also promoting the development of insulin resistance and obesity (pages 1490–1497).

A study in a mouse model of immune-mediated glomerular disease and in people with rapidly progressive glomerulonephritis shows activation of epidermal growth factor receptor (EFGR) signaling in podocytes by a molecule expressed in the kidney (pages 1242–1250). Blocking this axis may open new doors to treat inflammatory kidney conditions.

In the search for an improved vaccine to combat tuberculosis, a potent candidate has unexpectedly emerged that induces potent efficacy against mycobacterial infection in mice (pages 1261–1268).

BRCA1 germline mutations lead to an increased risk of breast and ovarian cancer, but the mechanisms by which the product of this gene functions as a tumor suppressor have remained elusive. Now, analysis of a missense BRCA1 variant shows that it can epigenetically regulate an miRNA implicated in cancer, providing new mechanistic insights (pages 1275–1282).

Mutations in the microsatellite of the chaperone heat shock protein 110 (HSP110) yield a mutant protein that counteracts oncogenic potential, enhances responsiveness to chemotherapy and associates with increased survival in individuals with colorectal cancers that arise through defective DNA mismatch repair (pages 1283–1289).

Memory T cells can be maintained for a lifetime, but the underlying mechanism has been hard to pin down. A new study identifies a subset of memory T cells with stem cell properties in humans and shows that these cells mediate a superior antitumor response in a mouse model of adoptive T cell therapy (pages 1290–1297).

Epilepsy complicates the clinical course of many patients with brain tumors, particularly gliomas. A mouse model of glioma now indicates that glioma cells release glutamate, causing tumor-related seizures (pages 1269–1274). Sulfasalazine, an approved therapeutic for Crohn's disease, can block glutamate release and improve seizures in these mice; therefore, this drug may also have potential antiepileptic effects in humans.

Peroxisome proliferator-activated receptors (PPARs) are important transcriptional regulators of genes involved in energy metabolism. Hydrolysis of cardiac lipid droplets by adipose triglyceride lipase (ATGL) is now shown to be required for PPAR-mediated gene regulation and mitochondrial function, suggesting new therapeutic possibilities for neutral lipid storage disease caused by mutations in ATGL (also known as PNPLA2) (pages 1076–1085).

The cancer stem cell (CSC) concept has provocative implications for our understanding of cancer biology and therapy. Its clinical relevance now receives a major boost from the finding that a stem cell–like or self-renewing gene expression signature can predict clinical outcome in acute myeloid leukemia (pages 1086–1093).

Imatinib represents the quintessential example of a targeted anticancer agent that directly suppresses the activation of oncogenic tyrosine kinases. Surprisingly, in the context of gastrointestinal stromal tumors (GISTs), the therapeutic effect of imatinib crucially depends on the reactivation of an anticancer immune response (pages 1094–1100).

Although the importance of epithelial to mesenchymal transition (EMT) is acknowledged in tumor metastasis, the contribution of the reverse process—MET—to cancer progression has been unclear. A new study shows that the miR-200 family regulates MET and metastatic colonization in breast cancer, suggesting that flexible transitions between EMT and MET, or epithelial-mesenchymal plasticity, may be crucial at different stages of metastasis (pages 1101–1108).