Reviews & Analysis

Moderate to severe asthma is difficult to treat because recurring bouts of inflammation in the lungs induce fibrosis, which reduces lung elasticity, gas exchange and responses to conventional therapy. A recent study identifies the tumor necrosis factor family member LIGHT as an essential mediator of airway fibrosis in a mouse model of chronic asthma (pages 596–603).

Hepatitis C virus puts about 130 million people worldwide at risk for severe liver disease, but no vaccine or broadly effective therapy yet exists. A new study identifies receptor tyrosine kinases as host factors required for hepatitis C virus entry—potentially opening the door for new antiviral strategies (pages 589–595).

Thiazolidinediones (TZDs) target peroxisome proliferator–activated receptor-γ (PPAR-γ) and are widely prescribed to treat type 2 diabetes but are associated with substantial weight gain. This side effect of TZDs is now shown to be mediated via brain PPAR-γ. These findings suggest an important role for brain PPAR-γ in obesity and have major implications for the clinical use of TZDs (pages 618–622 and 623–626).

Alum is the most widely used vaccine adjuvant, but its mechanism of action remains largely unknown. A recent study shows that alum interacts directly with membrane lipids on the surface of dendritic cells, triggering signaling cascades that promote CD4⁺ T cell activation and humoral immune responses (pages 479–487).

Axonal damage causes neurological defects in multiple sclerosis. In vivo imaging in mouse models of multiple sclerosis now shows a reversible and sequential process of focal axonal degeneration (FAD) (pages 495–499), suggesting the use of neuroregenerative as well as neuroprotective drugs as potential therapies for multiple sclerosis.

A new study shows that a candidate schizophrenia pathway, neuregulin-1–ErbB4 signaling, inhibits Src-mediated enhancement of synaptic N-methyl-D-aspartate receptor (NMDAR) function (pages 470–478). These results suggest that Src can have a pivotal role in NMDAR hypofunction in schizophrenia and thus might have potential therapeutic implications for this complex neuropsychiatric disorder.

A new study shows how SRC, a nonmembrane tyrosine kinase, is a common signaling node in trastuzumab resistance caused by different mechanisms in HER2-positive breast cancers (pages 461–469). A SRC inhibitor restored trastuzumab sensitivity in vitro and in mouse tumor models, suggesting a new way to tackle drug resistance in breast tumors.

Retinoic acid receptors inhibit chondrogenesis, but their ability to block the cartilaginous scaffold of heterotopic endochondral ossification has not been explored. A study in mice shows that agonists of retinoic acid receptor-γ potently inhibit heterotopic endochondral ossification, suggesting therapeutic potential in people with this condition (pages 454–460).

By the time diabetes is diagnosed, irreversible pathology is typically present, challenging therapeutic intervention. A reliable test for predicting diabetes risk could allow earlier implementation of intervention measures. Increased blood concentrations of amino acids are now suggested to predict risk of diabetes (pages 448–453), and amino acid profiling might also provide mechanistic insights into this disease.

A new potential breast cancer oncogene, ZNF703, has been identified in the chromosomal region 8p12 in humans, which is commonly amplified in an aggressive subtype of breast cancer. ZNF703 is a transcriptional repressor and regulates many genes that are involved in multiple aspects of the cancer phenotype, such as increased proliferation, invasion and an altered balance of progenitor stem cells.

Mitochondrial fission-fusion and trafficking are altered in the fatal neurodegenerative disorder Huntington's disease. Huntingtin is now shown to function directly in these processes by binding the mitochondrial fission factor dynamin-related protein-1 (DRP1). Mutant huntingtin binds more tightly to DRP1, leading to increased mitochondrial fission and neuronal death, highlighting DRP1 as a potential therapeutic target in Huntington's disease (pages 377–382).

Although the rapid development of drug resistance is a known problem with targeted cancer therapies, recent studies have uncovered other surprises with RAF kinase inhibitors. These drugs can paradoxically activate downstream ERK signaling in some settings, with important implications for their clinical use.

Neuroblastoma is a fatal childhood cancer, but lack of knowledge about the underlying causative genes has hampered the development of effective therapies. The identification of anaplastic lymphoma kinase (ALK) mutations as drivers of neuroblastoma has indicated that targeted therapy with ALK inhibitors might be a valuable strategy in the fight against this lethal cancer.

Therapeutic resistance is a key roadblock to effective cancer treatment and can occur through various mechanisms. A recent study characterized a previously unknown, reversible mechanism of drug resistance mediated by an altered chromatin state, suggesting that cancer cell populations can use a dynamic strategy to ensure their survival when challenged by therapeutic intervention.

A continuing quest in clinical oncology is to effectively eliminate tumors without major side effects. But drugs rationally tailored against specific tumors and predictive markers for patient selection are very limited, and their identification is challenging. A phase 1 study has provided proof of concept for the use of PARP inhibitors in tumors from individuals carrying BRCA mutations—a remarkable success in rational drug design and translational research.

X-box–binding protein-1 (XBP-1) increases insulin sensitivity by activating endoplasmic reticulum capacity during feeding to control glucose homeostasis, a function severely impaired in obesity. But XBP-1 can also increase glucose tolerance in obese and diabetic mice by blocking gluconeogenesis, independent of its effect on insulin sensitivity, opening new avenues for type 2 diabetes therapies (pages 356–365).

Inflammation is an important component of the tumor microenvironment; however, the mechanisms through which immune cells might promote tumorigenesis are unclear. A recent study indicates that B cells and antibodies have a key role in orchestrating macrophage-driven, tumor-promoting inflammation, suggesting that modulating the pathways involved might be of therapeutic benefit in cancers driven by chronic inflammation.

Recently characterized IDH1 and IDH2 mutations in leukemia and glioblastoma have introduced a fascinating cancer-specific role for metabolic genes essential to cellular respiration. Studies also link aberrant IDH1 and IDH2 activity to an altered metabolite profile, an observation that may have broad implications for both cancer epigenetics and clinical management of disease.

A microRNA decreases the expression of the adhesion molecule CD44 in prostate cancer stem cells (CSCs), blocking tumor growth and metastasis in mice (pages 211–215). Systemic delivery of this negative regulator may open new avenues for targeting CSCs to halt cancer.

Chronic inflammation is associated with obesity, but the pathways that mediate this phenomenon are not fully characterized. The nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (Nlrp3) inflammasome functions as a sensor to detect danger signals and induce downstream inflammatory signaling that contributes to obesity-associated conditions such as insulin resistance (pages 179–188).