Review Articles in 2013

The blood-brain barrier (BBB) has a key role in maintaining brain homeostasis and, thus, brain function. This Review outlines recent advances in understanding the development and maintenance of the BBB and the contribution of BBB disruption to various neurological diseases. It also discusses how such insights might be used to design new therapeutic strategies for BBB repair.

Adjuvants play an important part in vaccines, as they can enhance and shape antigen-specific immune responses. This Review discusses the benefits of adjuvants and recent advances in understanding their mechanisms of action. The authors also set out the clinical barriers to development of new adjuvants and offer suggestions for overcoming these hurdles to the advancement of next-generation vaccines.

There has been substantial progress in understanding the role of Hedgehog (Hh) signaling in cancer in recent years, as exemplified by the approval by the US Food and Drug Administration of the Hh pathway inhibitor vismodegib in 2012 for the treatment of basal cell carcinoma. This Review outlines these advances and charts the development of Hh inhibitors, providing a critical overview of how these drugs have fared in the clinic.

Despite the initial promise of cancer therapies targeted against the epidermal growth factor receptor (EGFR), tumors treated with these agents eventually develop resistance. In this Review, the authors outline the complex mechanisms by which tumors become resistant to EGFR-targeted drugs and antibodies and offer insights into new strategies that might be employed to circumvent therapeutic resistance.

Inhibitors of RAF kinase have shown substantial benefits in the clinic for the treatment of people with BRAF-mutant melanoma, but their utility is limited by the emergence of therapeutic resistance. In this Review, the authors provide a synthesis of the currently known mechanisms of resistance to RAF-targeted therapies and show how their model has implications for the development of more effective strategies to treat patients with BRAF-mutant tumors.

Cancer cells can alter and build a permissive microenvironment that supports the malignant behavior of a growing primary tumor and developing metastases. But the role of the players in the stroma is rather complex, and their functions are intertwined, requiring a strategy to normalize the microenvironment to halt cancer progression. Re-education of stromal cells that interact with tumor cells may be a promising therapeutic avenue to exploit a genetically stable part of the tumor.

Epithelial-mesenchymal transitions (EMTs) are a key requirement for cancer cells to metastasize and colonize in a new environment. Epithelial-mesenchymal plasticity is mediated by master transcription factors and is also subject to complex epigenetic regulation. This Review outlines our current understanding of the interactions between EMT-inducing transcription factors and epigenetic modulators during cancer progression and the therapeutic implications of exploiting this intricate regulatory process.

Increasing understanding of how tumor cells metastasize, what secondary organs are the targets of disseminating tumor cells and what molecular mechanisms are involved in the metastatic cascade can provide a road map to translate new biological insights into clinical practice. As tumor metastasis remains the main cause of death for patients with cancer, this is an unmet clinical need that requires a thorough examination of the most recent and relevant translational research.

There is much interest in brown and beige adipocytes, as their thermogenic activities can suppress weight gain and metabolic disease in rodent models. The authors review recent data that have provided new insights into the development and biology of brown and beige adipocytes and critically assess the possibilities for manipulating these cells to combat obesity and its associated diseases.

This Review provides an overview of the role of autophagy, a key lysosomal degradative process, in neurodegenerative diseases. The study of various neurodegenerative diseases has shown that defects in autophagy can arise at different points in the pathway, and this has implications for the successful modulation of autophagy for therapeutic purposes. The Review also discusses the latest developments in targeting alterations in autophagy as a therapeutic strategy for neurodegenerative diseases.

A new wave of antivirals to fight hepatitis C infection has helped patients achieve a good quality of life, but drug resistance, side effects and a lack of pan-viral genotype coverage still remains a problem. This Review discusses current clinical studies and potential targets of the virus life cycle to tackle these issues and puts forward a paradigm to develop second-generation effective antivirals and drug combinations for achieving the ideal regimen of an all-oral, interferon-free therapeutic cocktail.

Ongoing investigational studies aim to uncover new strategies to develop an effective vaccine to prevent hepatitis C infection. Advances have moved forward vaccine candidates, but technical and biological barriers posed by the virus still exist. This Review discusses how to better design vaccine trials and evaluate key components of protective immunity to achieve a working preventive vaccine.

There is much interest in the area of cardiac regeneration to replace cardiomyocytes lost in a heart attack. A number of recent studies have shown the feasibility of direct reprogramming, which allows one cell type to be directly converted into another cell type without going through a pluripotent intermediate step. In this Review, the authors review developments in direct reprogramming to cardiac cells in vitro and in vivo and compare the utility of these methods with pluripotent stem cell–mediated approaches.

During chronic infection caused by hepatitis C and B viruses, effector adaptive immune cells are exhausted and incapable of clearing the virus, but they can still contribute to liver inflammation in this setting. This Review discusses the regulatory role of nonspecific immune natural killer (NK) cells, which, along with other immune regulatory signals, help the host counteract liver disease progression and immunopathology by controlling virus-specific immunity.

In this Review, David L. Thomas discusses how recent therapeutic and diagnostic advances could be implemented in public health strategies to prevent viral hepatitis infections and treat existing infected patients. Despite the still increasing incidence and prevalence of hepatitis C infection, available tools may bring viral eradication a step closer toward becoming a reality.

This Review discusses recent developments in understanding the immune processes that occur at the fetomaternal interface to ensure fetal tolerance during pregnancy, including the roles of fetal trophoblasts, epigenetically modified decidual stromal cells and maternal innate and adaptive immune cells. The authors also explain how impairments in the maternal immune adaptation to pregnancy might influence pregnancy complication,s such as spontaneous miscarriage, as well as postnatal health of the child.

Thiazolidinediones (TZDs), which act through the nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ), are a widely prescribed class of drugs for type 2 diabetes; however, their use has been challenged by a number of side effects. Here the authors outline recent advances in our understanding of the modulation of the PPARγ pathway in metabolism and discuss how these insights might be used to explain the adverse side effects of TZD therapy and develop a new generation of safer PPARγ-targeting drugs.

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.