Volume 23 Issue 11, November 2017

A recent study describes a role for hypoxic signaling in the small intestine in the etiology of nonalcoholic fatty liver disease (NAFLD) and suggests that HIF-2α inhibitors may be an effective option for the treatment of this disease.

A recent study finds that the N⁶-methyladenosine (m⁶A) modifier METTL3 regulates proliferation and differentiation in myeloid cells and acute myeloid leukemia (AML).

A recent study identifies a population of CXCR5⁺ natural killer (NK) cells patrolling B cell follicles in simian immunodeficiency virus (SIV)-infected African green monkeys that might contribute to the lack of disease progression in this nonpathogenic model.

Recent research has identified sympathetic neuron–associated macrophages in adipose tissue that take up and degrade catecholamines released from neurons. Obesity and aging enhance this system, decreasing responses to cold stress and starvation.

Mowat, Scott and Bain discuss the functions of barrier-tissue macrophages in homeostasis and disease, and how these are shaped by their local environment.

Quantifying the total-body virus burden in HIV-infected individuals is necessary to understand viral persistence and guide development of cure strategies. Here, Estes et al. find a high burden of residual virus in tissues of SIV-infected monkeys and HIV-infected humans, and evidence of low-level viral replication, even under antiretroviral therapy.

Huot et al. investigate the differences in natural killer (NK) cells in lymph nodes during pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infection of cynomolgus macaques and African green monkeys (AGMs), respectively. Their findings suggest that NK cells are specifically recruited to follicles in AGMs and regulate SIV replication in the lymph node.

Hiroyuki Arai and colleagues characterize a new group of epoxy ω-3 fatty acid–derived proinflammatory lipid mediators, an enzyme mediating their biosynthesis and a signaling pathway by which they regulate a threshold of mast cell activation and anaphylaxis, revealing new targets for mast cell–mediated diseases.

Obesity induces hypoxia and upregulation of HIF-2α in the gastrointestinal tract, resulting in excess ceramide production and exacerbation of NAFLD.

Sympathetic neuron–associated macrophages act as a local sink for norepinephrine, leading to reduced thermogenesis and increased obesity.

Amplification of chromosome 1q21.3 distinguishes cells with tumor-initiating capacity that drive tumor recurrence across different breast cancer subtypes. A droplet digital PCR assay in circulating free tumor DNA identifies patients with early-stage cancer at high risk of relapse and predicts response to therapy in the metastatic setting. Pharmacological blockade of targets within this amplicon using a clinically available compound prevents tumor recurrence, suggesting a potential therapeutic approach to improve the clinical management of patients harboring 1q21.3-amplified breast tumors.

Concomitant overexpression of microRNAs miR-100 and miR-125b-1 within the host long non-coding RNA MIR100HG induces cetuximab resistance in cancer in the absence of previously associated genetic alterations. miR-100 and miR-125b target negative regulators of Wnt/β-catenin signaling and sustain drug resistance through feedback inhibition of GATA6 expression and this resistance can be overcome by pharmacological inhibition of Wnt activity. These findings, together with those by Tan et al. in the previous issue, highlight the emerging functional role of non-coding RNAs in modulating the response to anti-cancer therapies.

Combined inhibition of oncogene-driven glucose uptake and induction of cytoplasmic-p53 activity induces apoptosis in a subset of glioblastoma samples. In mice, PET imaging of glucose uptake predicts glioblastoma response to this combination therapy.

Microenvironmental pressures in glioblastoma select for glioma stem cells (GSCs) subpopulations that are maintained through preferential activation of BMI1 and EZH2 in different niches. Given the high degree of intratumor heterogeneity, combined pharmacological inhibition of Polycomb repressive complexes targets proneural and mesenchynmal GSCs and expands lifespan in mice, warranting the therapeutic evaluation of this approach in patients with glioblastoma.

Frequent loss-of-function mutations in KEAP1, a master regulator of the NRF2 antioxidant pathway, accelerate mutant KRAS driven lung carcinogenesis, but also impose a dependency of these tumors on glutaminolysis. Using a precision medicine–based approach, this work uncovers a metabolic vulnerability of KRAS–KEAP1-mutant lung cancers that can be therapeutically exploited using currently available glutaminase inhibitors and provides a scientific rationale for patient selection in clinical trials.

The N⁶-methyladenosine (m⁶A) modification in mRNAs, generated by the enzyme METTL3, controls normal human hematopoietic stem/progenitor cell differentiation and maintains the undifferentiated leukemic phenotype of human acute myeloid leukemia cells.

In rodent models of Alzheimer's disease (AD) and epilepsy, seizure-dependent induction of ΔFosB results in epigenetic silencing of calbindin. Hippocampal inhibition of ΔFosB or elevation of calbindin rescues spatial memory deficits in mouse models of AD.