Volume 19 Issue 2, February 2013

Stitches offer a suitable means of sealing up simple wounds. But when it comes to suturing tissues inside the body, the existing methods for closing wounds fall short. Elie Dolgin meets scientists taking inspiration from nature to develop the next generation of surgical adhesives.

In late September, ten pharmaceutical giants announced the formation of a Philadelphia-based nonprofit called TransCelerate BioPharma as a vehicle for sharing resources. This year kicked off with the appointment of its first chief executive, Dalvir Gill. He spoke with Roxanne Khamsi about his vision of how pharmaceutical firms can work together to simplify the process of multisite trials without sacrificing the quality of the data they collect.

It's up to stakeholders at every stage of therapeutic development—industry and academic researchers, policymakers, patient foundations and even patients themselves—to embrace the power of collaboration. Only then will we enable translational research and push much-needed treatments to the clinic faster.

There has been much focus on DNA mutations in tumorigenesis and tumor progression, but now a new study highlights a role for post-transcriptional changes in RNA in cancer. The authors show increased RNA editing of antizyme inhibitor 1 (AZIN1) in tumor tissues from patients with hepatocellular carcinoma and characterize a mechanism through which the expression of edited AZIN1 protein leads to increased cell proliferation (pages 209–216).

BH3 mimetics are a class of anticancer agents that hold the promise to trigger the central apoptotic machinery to set cancer cells on the road to ruin. Now, a new agent that selectively targets BCL-2, ABT-199, has been developed, with exciting preclinical and clinical results (pages 202–208).

Left ventricular noncompaction (LVNC) cardiomyopathy is a clinically and genetically heterogeneous disease that can be associated with substantial cardiovascular morbidity and mortality. A new study shows that mice with myocardial deletion of Mib1, which encodes a ubiquitin ligase in the Notch signaling pathway, have LVNC phenotypes and identifies MIB1 mutations in humans with LVNC (pages 193–201).

Modern medicine keeps unraveling new ways to investigate autoimmunity, leading to the production of boundless amounts of genetic, cellular and imaging data. Although the precision with which this information can define the etiology and mechanisms of a particular autoimmune disease is encouraging, much work lies ahead until all the knowledge acquired can be translated into the clinic. In 'Bedside to Bench', Calliope A. Dendrou, John I. Bell and Lars Fugger discuss the promises and limitations of genome-wide and next-generation genetic studies to provide further understanding of mechanisms driving autoimmune disorders and the role of experimental medicine in the new era of integrative clinical practice and personalized medicine. In 'Bench to Bedside', Lawrence Steinman argues the concept of a 'hub and spoke' pattern of T cell activation and organ targeting in multiple sclerosis, inflammatory bowel disease and type 1 diabetes. This paradigm suggests new ways to develop drugs to keep autoreactive T cells in the organ where activation occurs and preclude them from reaching the target organ and cause disease.

There is renewed enthusiasm in developing an HIV vaccine and in understanding the requirements to elicit broadly neutralizing HIV-specific antibodies. In May 2012, a workshop convened researchers to discuss the interplay of CD4⁺ T cell and antibody responses to help identify key questions and areas of research that can inform future vaccine development. This Perspective summarizes the discussion of three main topics on the role of CD4⁺ T cells in HIV vaccine design.

Malaria's death toll has been reduced as a result of global efforts over the last decade. Yet the rise of drug resistance and the plateauing of funding are still obstacles to eradicating the disease and reducing malaria burden. This review brings up the goals and challenges faced by researchers and the public health workforce and a way forward to effectively control and eliminate malaria.

The potential threat of parasite resistance to current antimalarials begs further research into antimalarial drug discovery to control disease progression. In addition, even when effective drugs are used, severe malaria symptoms still pose an important risk for death and cerebral residual disease in children. Further understanding of the pathophysiology of malaria and the biology of the parasite will open doors to new antimalarial treatments.

Wnt signaling is a major regulator during development. Genetic mutations affecting main regulators of this pathway have also emphasized the relevance of Wnt signaling in bone homeostasis after birth and diseases involving bone loss and fragility, such as osteoporosis. New therapies targeting Wnt signaling to increase bone formation are now under development.

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.

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.

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.

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.

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.

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.