Volume 16 Issue 7, July 2010

Last month, Carolyn Bertozzi became the first woman to win the prestigious Massachusetts Institute of Technology (MIT)-Lemelson Prize, a $500,000 award that honors midcareer inventors. Bertozzi, a chemical biologist, works to understand how sugars mediate cell-to-cell communication. Roxanne Palmer recently caught up with her to discuss Bertozzi’s sweet success with cell surface sugars.

Beginning in the 1970s, some hospitalized patients with schizophrenia began receiving drug injections that lasted for weeks in place of their daily antipsychotic pills. These extended doses helped them stick to their prescribed course of medicine but also carried the risk of causing irreversible neurological damage. Roxanne Khamsi reports on how newer versions of such long-acting injectables might radically change the treatment of ailments ranging from alcoholism to diabetes.

Ever since Edward Jenner discovered the smallpox vaccine two centuries ago, immunization efforts have almost exclusively focused on activating the immune system. But when it comes to multiple sclerosis and other autoimmune disorders, researchers hope to switch off—rather than ramp up—the body's defenses. Even an automotive service mogul has taken the idea on board. Elie Dolgin investigates how the idea of vaccination is being turned on its head.

It is not uncommon for potentially life-saving research data to be published years after being generated. But the setback to progress caused by the delay in releasing data is troublesome for people who selflessly participate in trials and desperately await new therapies. Scientists need to feel greater urgency to share their findings quickly, and they need additional avenues to facilitate this process.

Chromosomal translocations can promote cancers by eliciting the expression of fusion genes with oncogenic activity. The identification of translocations affecting RAF genes in prostate and gastric cancers and melanoma provides compelling evidence for the key role of RAF signaling in a subset of these cancers and suggests possible new avenues for personalized cancer therapy (pages 793–798).

Findings in mice and people suggest that glycosphingolipids have a role in the formation of large fluid-filled cysts in polycystic kidney disease. An inhibitor of glycosphingolipid synthesis may provide a potential therapy for this disorder, which often progresses to kidney failure (pages 788–792).

Ephrin-B2 is required for the formation of blood and lymphatic vessels, but the mechanism has been enigmatic. Two independent studies show that ephrin-B2 controls the internalization and signaling of two types of vascular endothelial growth factor (VEGF) receptors—thereby regulating VEGF-induced angiogenesis in normal and pathological conditions.

The stress response protein Rtp801 mediates damage to the lung in response to smoke. This finding might lead to new ways to treat chronic obstructive pulmonary disease and emphysema (pages 767–773).

Pregnancy increases the demand for insulin by various tissues in the body, a condition that can lead to gestational diabetes. To shield against this condition, insulin-producing beta cells proliferate in a process now shown to involve the local production of serotonin in response to lactogenic hormones (pages 804–808).

Basic research on the mechanisms of blood coagulation and the inflammatory response during tissue damage has revealed new potential targets for antithrombotic drugs. In 'Bench to Bedside', Charles T. Esmon examines three such studies, which offer the possibility of developing badly needed drugs that could block thrombosis without increasing the risk of hemorrhage. Esmon also raises the possibility that the new research could help explain why distal injury may contribute to protection of organs such as the heart, a process called 'remote conditioning'. In 'Bedside to Bench', Christian Weber takes a closer look at a clinical trial of remote ischemic conditioning, involving intermittent periods of occlusion and reperfusion on the arm. He examines evidence that cross-talk between cytokine and opioid receptors may underlie the effectiveness of this technique in protecting the heart from damage.

Rubin Tuder and his colleagues show that cigarette smoke induces expression of Rtp801 (also known as Redd1), a hypoxia-inducible protein that inhibits mTOR activity and enhances oxidative stress–mediated cell death. They also show that mice deficient in Rtp801 are protected from cigarette smoke–induced lung injury, thus suggesting the protein as a target to prevent emphysema.

Candida albicans is a fungal pathogen that causes serious systemic and mucosal infections in immunocompromised people. Blocking acetylation of histone H3 sensitizes C. albicans to antifungal agents, pointing to a new therapeutic strategy.

A prognostic gene expression signature predicts metastasis in individuals with sarcomas and other tumor types more accurately than existing tools.

Glycosphingolipid modulation may be a new approach to treat polycystic kidney disease. Blocking glucosylceramide accumulation with a glucosylceramide synthase inhibitor inhibits cyst formation in mouse models of the disease through inhibition of Akt-mediated signaling and by interfering with the cell cycle machinery.

Using pair-end transcriptome sequencing, this study provides the identification of Raf pathway gene rearrangements in a small proportion of prostate and gastric cancers and in melanomas. The fusion proteins show tumorigenic potential and represent a unique activating alteration of this oncogenic pathway, which seems to be mutually exclusive from known cancer-associated Raf mutations. This suggests that therapeutic Raf inhibition can be expanded to this fusion-harboring subset of solid tumors.

Immunologically targeting α-lactalbumin, a breast-specific protein highly expressed in breast carcinomas but absent from nonlactating mammary cells, provides protection against breast cancer in mice. This strategy may protect women against breast cancer in their post–child-bearing years, when lactation is readily avoidable and risk for developing breast cancer is high.

During pregnancy, women often become insulin resistant, thus requiring an expansion of pancreatic beta cell mass to provide more insulin. Michael German and his colleagues now report that lactogenic hormones drive the expression of serotonin in the beta cells to induce this increase in beta cell mass.

Transplant arteriosclerosis is a leading cause of transplanted organ dysfunction. Human regulatory T cells expanded ex vivo can prevent transplant arteriosclerosis in a mouse model by preventing the immune infiltration of the graft.

A critical donor organ shortage currently limits the treatment of patients with severe liver failure. Building on earlier work with decellularized hearts, Basak Uygun et al. have developed a transplantable liver graft using a decellularized liver matrix. This approach preserves the structural and functional characteristics of the native microvascular network, supports efficient recellularization and, when transplanted into rats, allows the viability and metabolic function of hepatocytes to be maintained.

Using the skin epidermis as a model for studies of epithelial biology and tumorigenesis and lentiviruses carrying RNAi or Cre recombinase, Beronja and colleagues describe a noninvasive, in vivo method for cell type–specific loss-of-function studies in the surface epithelia of mouse embryos. This approach can be used for the rapid functional assay of genes, the dissection of genetic interactions within complex regulatory pathways, and the study of the role of putative tumor suppressors and oncogenes in regulating growth control.