News & Views in 2013

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).

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).

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).

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).