Volume 23 Issue 8, August 2017

Clear links between human genes and susceptibility to influenza disease are scarce. A recent study uncovers a gene variant coupled to severe influenza, and shows how it hampers the expression of an antiviral gene that is key to immune cell survival.

A new study that uses a triple-drug combination to overcome a major mechanism of drug resistance in cancer provides insights into the evolutionary paths taken by tumors in the face of selective pressure.

Using interleukin (IL)-9-deficient mice, Rauber and colleagues unveil a crucial role for group 2 innate lymphoid cells (ILC2s) in the resolution phase of arthritic inflammation, opening up new therapeutic avenues for chronic inflammatory disease.

In this Review, David Fidock discusses malarial resistance to artemisinin-based combination therapies, among others, and presents strategies for designing new therapeutics and to overcome resistance.

Resistance to ERK signaling inhibitors in BRAF^V600E-mutant melanomas and lung cancers is achieved by parallel convergent mechanisms, including amplification of the mutant allele in extrachromosomal elements, that allow tumors to adapt while maintaining their intratumor heterogeneity. Intermittent treatment with a combination of RAF, MEK and ERK inhibitors imposes a higher selective pressure than sequential therapy and produces the strongest antitumor effects while minimizing toxicity. These findings warrant evaluating the effectiveness of this combinatorial regimen in patients, to improve treatment responses and delay the emergence of drug resistance.

Number of IL-9-expressing ILC2s are elevated in patients with inflammatory arthritis during remission, and these cells are critical in mice for the resolution of inflammatory arthritis via regulatory T cell induction. Delivery of DNA minicircles encoding IL-9 into inflamed joints ameliorates mouse experimental arthritis, suggesting possible therapeutic applications.

A complex of suPAR and high-risk variants of APOL1 acting on integrin signaling in the kidney contributes to APOL1-associated chronic kidney disease.

Repair of defects in the common bile duct is hampered by a lack of healthy donor tissue. Developing human extrahepatic cholangiocyte organoids and testing them in mouse models may provide a way to overcome this limitation.

The kinase Plk1 has been studied primarily as a mitotic regulator in dividing cells, but de Cárcer et al. find that Plk1 deficiency or inhibition in mice causes nonmitotic defects in the vasculature, including aortic aneurysm and rupture, as well as defective vascular smooth muscle contractility. These results recommend a note of caution in the clinical use of PLK1 inhibitors as anticancer agents.

IFITM3 encodes an antiviral protein that blocks entry of influenza A virus into cells. Paul Thomas and colleagues report that SNP rs34481144 in the 5′ UTR of IFITM3 is an expression quantitative trait locus for this gene and that the risk allele is associated with lower IFITM3 expression and severe influenza disease.

An HDR-independent therapeutic genome-editing approach corrected the splice-site mutation in Lama2 in a mouse model of congenital muscular dystrophy type 1A, and may be applied more broadly to correct splice-site mutations associated with other diseases.

FGF19 acts directly on skeletal muscle to increase its mass, and treatment with the hormone ameliorates muscle atrophy in three mouse models.

In a rat model of hydrocephalus triggered by intraventricular hemorrhage, Kristopher Kahle and colleagues show that TLR4–NF-κB-dependent inflammatory signaling in the choroid plexus causes hypersecretion of cerebrospinal fluid that drives hydrocephalus. Targeting TLR4–NF-κB-mediated signaling or the NKCC1–SPAK complex ameliorates hydrocephalus.