Reviews & Analysis

Recurrent disease after apparent 'cure' of primary tumors is a common factor that contributes to cancer-associated mortality. A new study suggests that an inflammatory cytokine signature may provide a clinical indication of emergent recurrent disease and, accordingly, may suggest how to select and deliver therapy targeted against the secondary tumor (pages 1625–1631).

Despite metformin being one of the most commonly prescribed drugs for the treatment of diabetes, how it elicits its therapeutic effects has remained mysterious. A new study in mice shows that inhibitory phosphorylation of acetyl-coA carboxylases Acc1 and Acc2 by the AMP-activated protein kinase (AMPK) is essential for the ability of metformin to improve insulin sensitivity and lower blood glucose in obesity (pages 1649–1654).

High blood ammonia, as seen in severe liver disease and urea cycle disorders, is neurotoxic and difficult to treat. A new study shows that the toxic effects are caused by impaired astrocyte potassium buffering—not astrocyte swelling, as previously thought—and can be partially blocked by the diuretic bumetanide (pages 1643–1648).

Cell-mediated activation of latent TGF-β1 is a key promoting event in fibrosis in all organs. A new study shows that specific targeting of the αv subunit of integrins in fibrogenic myofibroblasts effectively reduces developing and established fibrosis in liver, kidneys and lungs (pages 1617–1624).

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.

Understanding the molecular mechanisms that govern diabetes-induced loss of kidney function is crucial. A new study shows that in mouse models of diabetes, sirtuin 1 (Sirt1) in the proximal tubules of the kidney can modulate the expression of podocyte Claudin-1, a key regulator of albuminuria and glomerular function (pages 1496–1504).

Autophagy and apoptosis are ancient processes that regulate cell fate under normal and disease conditions. A new study in mice identifies mammalian Ste20-like kinase-1 (Mst-1) as a missing link that interfaces between these pathways for cell survival and death during cardiac stress (pages 1478–1488).

In fragile X syndrome, the absence of fragile X mental retardation protein (FMRP) allows the production of certain proteins to go unchecked in the brain. A recent study in mice suggests that bringing excessive translation into balance may provide a key to treating this syndrome (pages 1473–1477).

An endogenous molecule secreted by macrophages during stress is a new mediator for the wave of inflammation triggered during hemorrhagic and septic shock. This finding suggests a potential drug target to reduce organ injury and death after shock (pages 1489–1495).

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.

Aspergillus fumigatus is a fungus that is associated with a severe form of asthma, although the precise immunological basis for this disease is unclear. A new study in mice shows that natural killer T (NKT) cells are crucial for progression of A. fumigatus–induced asthma and also identifies a glycolipid antigen from this fungus that seems to drive this NKT cell–mediated inflammatory response (pages 1297–1304).

Glioblastoma multiforme (GBM) is the most common type of aggressive malignant brain cancer. The current lack of successful therapeutics means that this disease has a dismal prognosis. However, a new study in mice offers hope for patients with GBM by demonstrating the efficacy of a novel drug that targets GBM-associated macrophages (pages 1264–1272).

A signaling cascade is activated in podocytes to induce survival and cope with stress during advanced glomerular disease, a new study shows. The findings may also explain why the immunosuppressor sirolimus, an inhibitor of this pathway, can cause proteinuria in a subset of patients with chronic kidney disease (pages 1288–1296).

After myocardial infarction (MI), circulating B cells produce the chemokine Ccl7, which mobilizes inflammatory monocytes from the bone marrow into the blood, after which they are then recruited to the injured heart, a new study shows. B cell depletion after MI limits myocardial injury and improves heart function, suggesting a new approach for the management of acute MI (pages 1273–1280).