Volume 17 Issue 8, August 2011

On 22 June, María Blasco, best known for her research on the enzymes that maintain telomeres, became the new director of the Spanish National Cancer Research Centre (CNIO). Elie Dolgin spoke with her about her plans for the 13-year-old agency.

International collaborations are common in science. But some researchers go one step further, holding formal appointments in two (or more) countries—in some cases, on opposite sides of the globe. Cassandra Willyard examines what researchers have to gain from such far-flung arrangements.

There are no magic bullets in the fight against cancer. But by targeting proteins found almost exclusively in tumor cells and the testes, researchers may have discovered the closest thing yet. Megan Scudellari explores how a handful of young investigators hope to turn magic into reality.

A recent serious outbreak of Salmonella linked to clinical and teaching microbiology laboratories highlights the dangers of working with laboratory pathogens—but it is probably not an isolated occurrence. Without a better system for reporting infections resulting from laboratory exposures, we risk seeing more of these types of outbreaks.

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).

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.

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.

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).

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).

Genetic mutations can cause numerous diseases. These alterations affect not only protein-coding genes but also regions that were until recently thought to be trivial in disease. In 'Bedside to Bench', David Salzman and Joanne Weidhaas examine a human study showing how a silent mutation impairs the binding of miR-196, increasing the risk for Crohn's disease. Therefore, alterations of miRNA target sites as pathogenic mechanism begs further investigation. miRNAs themselves can also be the root of disease. In 'Bench to Bedside', Carlo Croce peruses a study in vivo showing evidence of tumor addiction to miR-21 in a mouse model of cancer, which highlights the role of miRNAs as initiators of disease. Targeting these drivers will help to develop effective drugs.

Patients undergoing radiation treatment for Hodgkins's lymphoma are at increased risk of developing secondary malignancies with time. This genome-wide analysis identifies genetic polymorphisms associated with increased risk of secondary malignancies in treated children. The risk alleles result in decreased radiation-mediated induction of PRDM1, a tumor suppressor transcription factor, leading to impaired repression of oncogenic drivers such as MYC.

This report identifies PICT1 as a new regulator of p53. PICT1 binds the ribosomal protein RPL11 and prevents its release from the nucleolus, precluding RPL11 from inhibiting MDM2 activity. Loss of PICT1 increases p53 abundance and protects from tumorigenesis in mice. PICT1 is also a prognostic marker in human cancers. This p53-dependent protumorigenic function is in contrast with previous reports suggesting a tumor-suppressor role for PICT1.

Focal segmental glomerulosclerosis (FSGS), or kidney scarring, is difficult to treat and is often only curable with kidney transplantation. However, FSGS often recurs after transplantation, and ~40 years ago, an unknown soluble factor in the recipient was hypothesized to exist to explain such cases. Jochen Reiser and his colleagues use data from human and mouse studies to show that soluble uPAR may be the long-sought-after soluble factor.

Notch, a molecule widely known for its role in development and cancer, regulates hepatic glucose metabolism by offsetting excessive glucose production. Given that a series of Notch antagonists are in clinical trials against cancer, they could also be useful against type 2 diabetes.

Charcot-Marie-Tooth type 2 disease is characterized by peripheral axon loss and motor and sensory dysfunction. Constantin d'Ydewalle et al. demonstrate that these abnormalities are caused by drops in tubulin acetylation and can be normalized in mice with drugs that restore this acetylation.

Follicular helper T (T_FH) cells provide survival and selection signals to germinal center B cells. Here, Carola Vinuesa and colleagues describe a regulatory T cell subset that co-opts the differentiation program of T_FH cells and limits their numbers in vivo. Ablation of these T_FH-like, T regulatory cells alters the number of antigen-specific B cells suggesting regulatory T cells modulate germinal center responses.

Germinal center B cell development is promoted by T follicular helper cells. Chen Dong and his colleagues show that Foxp3⁺ regulatory T cells expressing Bcl6 and CXCR5, two molecules highly expressed in T follicular helper cells, are present in humans and mice and arise from natural regulatory T cells. In vivo, these CXCR5⁺Bcl6⁺ regulatory T cells modulate germinal center responses.

Specific variants of the human leukocyte antigens HLA-B27 and HLA-B57 are associated with control of HIV-1 infection, but the mechanisms responsible for this protection are not clear. Here, Elahi et al. show that CD8⁺ cytotoxic T cells restricted by these HLA variants are less susceptible to suppression by and are able to kill regulatory T cells, which may account for their sustained proliferative capacity during chronic HIV-1 infection.

How alum acts as a vaccine adjuvant continues to perplex. Here Marichal et al. now report that alum induces host cell death and release of genomic DNA, which acts as an endogenous damage-associated molecular pattern that stimulates antibody and T cell responses

The widely prescribed beta blocker carvedilol has strong antiarrhythmic effects on the heart, but the underlying mechanisms have been unclear. Qiang Zhou et al. now show that carvedilol, unlike other beta blockers, is also able to block proarrhythmogenic spontaneous calcium waves by directly inhibiting the calcium release channel RyR2. By generating new carvedilol analogs that inhibit RyR2 but not β-adrenergic receptors, the authors provide evidence that antiarrhythmic therapy might be optimized by combining agents that are individually selective for these two targets.

Progress in understanding coronary artery disease has been hampered by the inability of current approaches to interrogate the human coronary wall at cellular-level resolution. Here, Liu and colleagues introduce a second-generation form of OCT, called ↘OCT, that provides three-dimensional images of human coronary atherosclerosis at an axial resolution of only 1 ↘m—an order of magnitude greater than that provided by standard OCT systems.

Ready access to diagnostic tests that work well under remote field conditions is a major barrier to improving the health of people in the developing world. Here, Curtis Chin and his colleagues have developed a chip-based, microfluidic device and handheld reader for the simultaneous and rapid diagnosis of HIV and syphilis that uses only 1 μl of unprocessed whole blood and that was successfully field tested in Rwanda.