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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).
Second cancers are a substantial clinical problem in survivorship. A genome-wide association study (GWAS) in survivors of Hodgkin's lymphoma treated with radiotherapy now identifies a region of susceptibility on chromosome 6q21 (pages 941–943), paving the way for further investigations of the complex interplay between genetic susceptibility and environmental exposures involved in the development of second cancers.
The ribosomal protein RPL11 can block cell growth by boosting function of the tumor suppressor p53 in response to ribosomal stress, but the connection of this role with cancer has been obscure. New findings show that the nucleolar protein PICT1 can sequester RPL11, impairing p53 activation and favoring tumor growth (pages 944–951).
Certain human leukocyte antigen (HLA) alleles are associated with vigorous human immunodeficiency virus (HIV)-specific CD8+ T cell responses and good clinical outcomes. A new study suggests that CD8+ T cell–mediated killing of regulatory CD4+ T cells may partially explain how people with these protective alleles control HIV-1 replication (pages 989–995).
How B cell tolerance is retained during somatic hypermutation in germinal centers is incompletely understood. Two studies now show that Foxp3+ regulatory T cells undergo functional specialization to limit the magnitude of the germinal center response, and they may contribute to our understanding of how germinal center–mediated autoimmunity is prevented (pages 975–982 and 983–988).
Spontaneous calcium release from intracellular stores can trigger irregular heart beats and sudden death. A new study shows that the heart failure drug carvedilol prevents irregular heart beats by a unique action on calcium release channels (pages 1003–1009).
For many years, investigators have been searching for an elusive circulating factor that could cause the common kidney disease focal segmental glomerulosclerosis (FSGS). The finding that a circulating, soluble form of the urokinase receptor (suPAR) can activate podocyte β3 integrin, leading to FSGS pathology (pages 952–960), provides new insights into this disease and may have important clinical implications.
To repair the immune-mediated demyelination that occurs in people with multiple sclerosis, strategies to enhance remyelination are being considered as a possible therapy. A new study shows that inhibition of death receptor 6 (DR6) signaling increases the maturation and survival of oligodendrocytes, thus promoting remyelination in rodent models of demyelination (pages 816–821). Blocking DR6 might provide new therapeutic opportunities for the treatment of demyelinating diseases.
Despite intensive study, the mechanisms of pathogenesis in inflammatory bowel diseases (IBDs) remain poorly understood. An innate T helper type 17 (TH17) response that requires nucleotide oligomerization domain (Nod)-like receptors and is primed by commensal bacteria is now shown to be crucial for controlling intestinal bacterial pathogens in a mouse model (pages 837–844). Thus, dysregulation of this protective immune response may be important in IBD development.
A recent study challenges the view that radiation-induced apoptosis is beneficial in tumor therapy by showing that caspase 3–mediated apoptosis in response to ionizing radiation activates a growth signaling cascade in tumor cells, thereby stimulating tumor repopulation (pages 860–866). These results may have important implications for the clinical use of radiotherapy or chemotherapy to induce apoptosis in tumors.
Obesity and high blood pressure are commonly associated. A study in mice now shows that hypothalamic inflammatory pathways may be the link connecting these two disorders and a potential target to uncouple obesity-related hypertension from weight gain (pages 883–887).
