Reviews & Analysis

DNA that is shed by dead tumor cells into the blood, termed circulating tumor DNA (ctDNA), is a rich resource that could potentially be used for cancer diagnostics and monitoring. A new study describes a sequencing-based method that improves upon the sensitivity and specificity achieved by past techniques for detecting ctDNA and that can be used for monitoring of disease burden in patients with non–small-cell lung cancer (pages 548–554).

Anemia is a debilitating condition that can be complicated by ineffective erythropoiesis. Two new studies identify GDF11 as a regulator of erythropoiesis and show that its inhibition in mouse models of anemia with ineffective erythropoiesis restores normal erythropoietic differentiation and alleviates anemia (pages 398–407 and 408–414).

Pharmacologic modulation of iron metabolism may be a potential strategy to control infection caused by the intracellular bacteria Salmonella enterica var. Typhimurium (S. typhimurium) (pages 419–424). The molecular mechanism involves the estrogen-related receptor γ (ERRγ) in the liver, which can be targeted with an inverse agonist to improve survival of infected animals.

In the mammary gland, the stiffness of extracellular matrix (ECM) collagen is thought to influence tumor progression and clinical outcome. A new mechanism orchestrated by a microRNA circuit is shown to mediate the physical effects of the microenvironment on tumor cell progression. The findings may explain how increased breast matrix stiffness is associated with poor survival and could help identify women with aggressive breast cancer (pages 360–367).

Bariatric surgery reduces the weight of morbidly obese individuals and exerts beneficial effects on associated metabolic disorders such as type 2 diabetes. However, despite growing traction in this area of metabolic research, questions remain as to the mechanisms that lead to these benefits. New findings propose that the bile acid–activated nuclear receptor FXR mediates the metabolic improvement seen after one particular bariatric surgery approach and that this may involve alterations in the microbiome.

Decreased muscle stem cell function in aging has long been shown to depend on altered environmental cues, whereas the contribution of intrinsic mechanisms remained less clear. Two new studies now reveal that cell-autonomous changes in the p38 mitogen-activated protein kinase pathway are major phenotype determinants of aged muscles stem cells (pages 255–271).

The cure and elimination of malaria caused by Plasmodium vivax is hindered by the threat of relapse infections from undetectable dormant forms of the parasite in the liver. In a new breakthrough, using a related parasite, Plasmodium cynomolgi, it has been shown that the small nongrowing forms of the parasite, termed hypnozoites, can be reactivated in primary simian hepatocytes that have been infected and maintained in culture for 40 days, providing a system to study this parasite form with the development of potential new antihypnozoite drugs in mind (pages 307–312).

Neural circuits are able to modulate immune responses by detecting inflammatory mediators and relaying signals back to the immune system. Here, in a mouse model of sepsis, the authors show that the immune responses can be modulated by electroacupuncture, which stimulates a neural circuit that results in the release of dopamine. The mechanism, like the inflammatory reflex, is neither sympathetic nor parasympathetic. Their results show a potential way forward in developing therapies for sepsis in dopamine agonists (pages 291–295).

The expression of antibodies to protect against an infectious disease can be achieved by the injection into the host of vectors carrying the gene to the relevant antibodies. Here the authors demonstrate the applicability of this technique to protection from HIV in a humanized mouse model, showing this to be a valid route to pursue in vaccine development for humans (pages 296–300).

Interferon-β (IFN-β) is widely used to treat multiple sclerosis (MS), but its mechanism of protection remains obscure. A new study shows that IFN-β induces FoxA1⁺ regulatory T cells, a new regulatory T cell population, which suppress conventional T cells via programmed cell death 1 ligand 1. This cell subset limits disease in a mouse model of MS and was found in patients with MS who responded to IFN-β therapy (pages 272–282).

Modification of a natural product with antibiotic properties to block its efflux from Mycobacterium tuberculosis results in a new drug candidate for tuberculosis with a promising therapeutic profile in mice (pages 152–158).

A new study in mice provides a link between dietary fiber intake, amounts of intestinal and systemic short-chain fatty acids, changes in the microbiome and allergic responses in the airways. The findings support the growing appreciation of a potential therapeutic role of diet in treating allergic diseases (pages 159–166).

Retinoic acid and arsenic trioxide cure individuals with acute promyelocytic leukemia (APL). In mouse models, these drugs eradicate tumor cells by activating the tumor suppressors p53 and PML to induce senescence of cancer cells (pages 167–174).

Numerous neurodegenerative diseases show deposition of protein aggregates, which are thought to cause neuronal damage. This Review discusses how cell-to-cell transmission of these pathogenic misfolded proteins is involved in initiation and progression of the disease and examines the clinical relevance of different strains in the heterogeneity of neurodegenerative disorders.

The concordant epidemics of asthma and obesity are both associated with inflammation, and obesity has been shown to be an independent risk factor for asthma. A new study in mice indicates that part of the immunological connection between obesity and asthma involves inflammasome activation and production of the cytokine interleukin-17 by innate lymphoid cells in the lung (pages 54–61).

Under most circumstances, Foxp3⁺ regulatory T (T_reg) cells are a stable T cell population essential for maintaining self-tolerance. A study now shows that the inflammatory environment in autoimmune arthritis induces conversion of a subset of Foxp3⁺ T cells into interleukin-17–producing cells that contribute to disease pathogenesis (pages 62–68).

Many tumors display a hierarchical organization that is maintained by a self-renewing 'cancer stem cell' population. A new study in mice shows that targeting the self-renewal regulator BMI-1 abrogates the tumorigenic capacity of colon cancer stem cells, providing a new therapeutic strategy (pages 29–36).

Liver-stage Plasmodium infection triggers a type I interferon transcriptional program in hepatocytes that amplifies an innate immune response within hepatic myeloid cells. This minimizes liver parasite load and delays the release of disease-causing parasites into the bloodstream (pages 47–53).