Reviews & Analysis

Synthetic lethality describes a situation in which defects in either one of two genes are not detrimental, but combining defects in the two genes is lethal. The targeting of BRCA-deficient tumors by PARP inhibitors is the first clinical example utilizing the principle of synthetic lethality to treat cancer. Despite the promise of this approach, a number of resistance mechanisms have been identified, and this Perspective describes these mechanisms and their clinical relevance.

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.

Interleukin-17 (IL-17) released in the tumor microenvironment in response to drugs blocking vascular endothelial growth factor (VEGF) triggers stromal-derived inflammatory and VEGF-independent angiogenic programs that induce the drug refractoriness found in cancers resistant to anti-angiogenic therapy (pages 1114–1123).

Macrophages accumulate in atherosclerotic lesions during the inflammation that is part of atherosclerosis development and progression. A new study in mice indicates that the accumulation of macrophages in atherosclerotic plaques depends on local macrophage proliferation rather than the recruitment of circulating monocytes (pages 1166–1172).

TACE-mediated proteolysis is a key event interfering with both Alzheimer's and prion diseases. A new study shows that phosphoinositide-dependent kinase-1 (PDK1) is activated by cellular prion protein, which alters membrane-associated TACE levels, thereby influencing both Alzheimer's and prion pathologies (pages 1124–1131).

The fibroblast growth factor 21 (FGF21)–β-Klotho pathway orchestrates a switch to oxidative metabolism during fasting and starvation and has been implicated as a signal connecting nutrition, growth, reproduction and longevity. Two new studies in mice show that Fgf21 interacts directly with the brain circadian clock to coordinate activity and reproduction as part of the adaptation to fasting (pages 1147–1156).

ETS gene fusions and PTEN loss are common events in prostate cancer, but their interactions are not well understood. A new study in mice suggests that overexpression of ETS in the setting of PTEN loss increases androgen receptor binding and restores androgen receptor transcriptional activity (pages 1023–1029).

Pathologic fatty liver paradoxically accompanies obesity and type 2 diabetes despite the crippling of insulin signaling, which is normally required for fat synthesis. The developmental signaling protein Notch is a hidden regulator of lipogenesis that amplifies signal transmissions to fat production in these metabolic diseases (pages 1054–1060).

Whereas diabetes and hypertension predominate as the etiology of chronic kidney disease (CKD), all primary causes share a common progression pathway due to scarring or fibrosis. Understanding what cells are the sources of scar-forming cells is of utmost importance (pages 1047–1053).

A new study shows that the orphan nuclear receptor liver receptor homolog 1 (LRH-1) wires the postovulatory rise in progesterone production to progesterone-dependent preparation of the endometrium for pregnancy, a process termed decidualization. Lack of Lrh-1 activity in either the ovary or uterus has catastrophic consequences for reproduction in mice (pages 1061–1066).

Excitatory neurotransmission through NMDA receptors (NMDARs) has a pivotal role in healthy brain function, and its dysfunction has long been implicated in the pathogenesis of neurodegenerative disorders, including Huntington's disease. A new study uncovers a molecular link between mutant huntingtin and aberrant trafficking of an unconventional NDMAR subunit (GluN3A). Targeting this disease mechanism in a Huntington's disease mouse model had multiple therapeutic benefits (pages 1030–1038).

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.

There is much interest in the applications of pluripotent stem cells for regenerative medicine. In this Perspective, the authors discuss the factors that might contribute to the potential risk of tumorigenicity from pluripotent stem cell therapies. They also outline recent developments in techniques that allow the sorting of tumorigenic species from nontumorigenic cells and offer a viewpoint into the future hurdles for moving pluripotent stem cell–based therapies from bench to bedside.

A new study provides an example of the delicate balance between stem cell migration, differentiation and maintenance in the context of skin wounding. In mice, wounding or ultraviolet irradiation induces melanocyte stem cells in the hair follicle to leave their niche before cell division and migrate up the follicle to differentiate into functional melanocytes, thus providing a protective pigmented barrier (pages 924–929).

Metabolic alterations, such as those caused by mutations in the enzyme isocitrate dehydrogenase (IDH), define a clinically distinct subset of primary brain cancers. Expression of BCAT1 is now reported as a new metabolic change defining brain cancers without IDH mutations (pages 901–908).

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.

Persistence of hepatitis C virus contributes to chronic infection, which can lead to liver fibrosis and even liver cancer. Different factors, such as host genetics and immunity and viral immune evasion strategies, account for the outcome of the infection and the patient response to antivirals. This Perspective discusses how the interaction of these factors modulates viral immunity and how they might be used to identify the key targets to mount an effective immune response that will clear the virus and improve drug response.