Volume 19 Issue 8, August 2013

On 5 July, the UK government announced the launch of a new nonprofit company set up by the Department of Health called Genomics England, which aims to sequence 100,000 whole genomes, with linked clinical data, from people with cancer, rare diseases and infectious diseases—all by the end of 2017. Elie Dolgin spoke with Sir John Chisholm, the executive chair leading the effort.

An experimental approach promises to change the future for boys diagnosed today with cancer, allowing them to genetically father children of their own instead of facing a life of infertility. But will the science be ready when the children grow up, or are researchers subjecting families to another stressful decision for a hope that might not pan out? Alison McCook reports on the cutting-edge science—and controversy—surrounding the freezing of prepubescent tissue.

Doctors often dismiss drugs as ineffective if they fail to outperform dummy pills in randomized trials. That's a mistake. When active medicines have few side effects and produce a strong placebo effect, such drugs, even if they prove just slightly better than placebo, should be embraced for the relief they can bring to patients who have few safe alternatives.

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).

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).

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).

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).

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).

How eosinophils function in different tissues during health and disease is not completely understood. On the one hand, they seem to be crucial in inflammatory disorders, which suggests that pathways related to their activation and regulation may be potential therapeutic targets. In asthma, the role of these cells is well known; however, airway inflammation owing to increased eosinophils in lung tissue in nonallergic asthma has only recently started to be in the limelight. In 'Bedside to Bench', Guy G. Brusselle, Tania Maes and Ken R. Bracke peruse the disease pathway triggering eosinophilic inflammation in nonallergic eosinophilic asthma and the potential targets that may lead to effective therapies. The authors also discuss a clinical study that highlights the need to phenotype patients using cellular and molecular markers to improve treatment responses. However, on the other hand, a recent study has also shown a homeostatic role of eosinophils in metabolism in fat tissue. In 'Bench to Bedside', Clare M. Lloyd and Sejal Saglani examine evidence that hints at the crucial role of the location of eosinophils in different tissues such as lung, where they cause inflammation, and visceral fat, where they improve glucose homeostasis. Clinical data that correlate lung tissue eosinophilia with obesity may spur new research to shed light on the role of these inflammatory cells in obese individuals with asthma and on how to improve treatments in these patients.

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.

Eosinophilic esophagitis (EoE) is characterized by esophageal eosinophilia, but the underlying mechanisms promoting eosinophil accumulation remain unclear. David Artis and his colleagues describe a new mouse model of EoE-like disease. The development of EoE-like disease is dependent on thymic stromal lymphopoietin (TSLP) and basophils, whereas inhibition of TSLP or depletion of basophils attenuates established disease. Moreover, individuals with EoE have increased TSLP expression and basophils in the esophagus, suggesting that the TSLP-basophil axis can be targeted in patients with EoE.

During B cell development, cells that fail to productively rearrange their immunoglobulin VH-DJH gene segments to generate an in-frame junction that codes for a functional pre-B cell receptor are deleted. Markus Müschen and colleagues now report that Bach2 is a key component of this pre-B cell receptor checkpoint that enables the elimination of normal and transformed B cells with nonfunctional V(D)J rearrangements by regulating the expression of p53.

Studies on a new conditional mouse model reveal that ETS transcription factors, which are often mutated in prostate cancer, cause transformation by altering the androgen-receptor cistrome, priming the prostate epithelium to respond to upstream signals such as PTEN loss.

Huntington's disease is a neurodegenerative disorder associated with glutamate receptor dysfunction. Now Isabel Pérez-Otaño and colleagues report that the HTT protein that aggregates in the brains of individuals with the disease disrupts the ability of the adaptor protein PACSIN1 to keep the glutamate receptor subunit GluN3A away from the surface of neurons.

Bart Staels and his colleagues show that the transcription factor Rev-erb-α is highly expressed in oxidative muscle and, via loss- and gain-of-function experiments, including pharmacological activation, that it plays a key partin regulating the oxidative capacity of the muscle and exercise endurance.

Myofibroblasts are associated with organ fibrosis, but their origin and functional role remain unknown. Using multiple genetically engineered mice, the authors found that in the kidney, myofibroblasts arise from multiple sources—resident fibroblasts, bone marrow, endothelial cells and epithelial cells. Targeting these different populations may therefore be required to inhibit the accumulation of myofibroblasts in kidney fibrosis.

Hepatic insulin resistance, a hallmark of type 2 diabetes, results in elevated blood sugar concentrations and fatty liver disease. Domenico Accili and his colleagues now show that inhibition of Notch signaling in the liver dampens the pathways leading to both conditions, thus improving these aspects of diabetes.

Liver receptor homolog-1 is an orphan nuclear receptor. Murphy and colleagues now show that this protein is crucial for different phases of pregnancy, including implantation and maintenance of the developing fetus, in mice, as well as for the proper function of human endometrial cells in culture.

There is a pressing need for techniques that can be used for the noninvasive assessment of response to therapy and staging of disease. As many pathological conditions are associated with disordered glucose metabolism, such as diabetes, stroke and cancer, Simon Walker-Samuel and his colleagues have developed a noninvasive MRI-based method for imaging glucose uptake in vivo termed glucose chemical exchange saturation transfer (glucoCEST). This potentially cost-effective approach does not require the use of radiolabeled glucose analogs or ionizing radiation and allows nonlabeled glucose to be imaged at physiological quantities.