Brief Communications

Understanding how and where HIV-1 infection persists in the body is crucial for efforts to eradicate the viral reservoir. Now Mathias Lichterfeld and his colleagues report that HIV-1 can infect CD4⁺ T memory stem cells (T_SCM cells) and that infected T_SCM cells constitute a stable component of the viral reservoir in individuals treated with antiretroviral therapy.

The authors employ targeted next-generation sequencing to identify driving oncogenic alterations in patients with lung cancer with no known oncogenes. They discover two gene fusions involving NTRK1 that lead to constitutive activation of the kinase TRKA and can drive transformation. The fusions can be targeted with available kinase inhibitors and may represent therapeutic targets.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of the translational repressor protein FMRP. Now, Joel D. Richter and his colleagues report that knocking down the expression of the translational activator protein CPEB can restore normal levels of translation and rescue behavioral deficits in a mouse model of FXS.

Mutations in mitochondrial DNA that inhibit the normal function of this organelle can result in disease if a sufficient percentage of mitochondria in the body's cells harbor such alterations. Using transcription activator–like effector nuclease (TALEN) technology, Carlos Moraes and his colleagues show that mutant mitochondria can be selectively targeted and eliminated, allowing for a sufficient percentage increase of normal mitochondria and thus restoration of normal respiration in a cell-based model.

An adeno-associated virus (AAV) vector encoding a variant of human lipoprotein lipase was recently approved in Europe as the first gene therapy for the treatment of LPL deficiency. Here Manfred Schmidt and his colleagues report their analysis of AAV integration sites after injection of the gene therapy construct in LPL-deficient patients and in mice.

Rifampicin and isoniazid are often used together as a co-therapy to treat tuberculosis, but their combined use often leads to hepatoxicity in humans. Xiaochao Ma and colleagues now report the mechanisms behind this side effect, thus opening a possible avenue to the safer use of these effective drugs.

Patients with sickle cell disease or β-thalassemia are treated with drugs that aim to reactivate production of fetal hemoglobin, but these drugs are not effective in all patients and have side effects. Lihong Shi et al. identify a new therapeutic strategy for these anemias, showing that a drug used to treat depression, tranylcypromine, can raise fetal hemoglobin levels in human erythroid cells and transgenic mice harboring the human β-globin locus, most likely by inhibiting a lysine demethylase that controls fetal globin gene expression.

Doxorubicin, which induces tumor cell death through effects on topoisomerase-II, is a commonly used chemotherapeutic agent but has the substantial drawback of causing cardiotoxicity. Edward T.H.Yeh and his colleagues now show that doxorubicin-induced cardiotoxicity in mice is due to the deleterious effects of doxorubicin on topoisomerase-IIβ in cardiomyocytes, leading to alterations in gene expression, mitochondrial dysfunction and cell death.

A slight mechanical pressure applied to healthy skin results in blood vessel dilation, preserving blood flow. Defects in this vasodilatory response lead to an increased risk of pressure ulcers. Fromy et al. identify the neuronal mechanosensor that mediates this response in both rodents and humans: the ion channel Asic3.

Morphine loses its ability to fight pain after chronic use. Now, Howard Gutstein and his colleagues report that morphine induces release of PDGF, and blockade of PDGFR signaling can reestablish morphine analgesic efficacy in rats that have become tolerant.

Using high-coverage targeted next-generation sequencing, this report provides a catalog of genetic alterations in colorectal and lung cancers, identifying previously unknown alterations, such as JAK2 mutations and KIF5B-RET fusions, that may represent druggable targets.

The authors report a new type of genetic alteration in lung adenocarcinoma. Fusions of KIF5B with RET kinase are found in 1–2% of lung cancer patients, segregate from other known alterations and can potentially be targeted using RET kinase inhibitors.

Through an integrated screening system, the authors catalog ALK and ROS1 fusions in lung cancer and identify a new class of fusions involving KIF5B and RET that may represent new therapeutic targets in adenocarcinoma.

This report uncovers a direct link between cancer-driving inflammation and DNA methylation by showing that PGE₂ regulates the expression of DNA methylases, resulting in silencing of tumor-suppressor genes. The authors suggest that DNA methylation is an important component of the pathogenic effect of inflammatory signaling in colorectal cancer.

By modeling acquired resistance to the EGFR antibody cetuximab in metastatic colorectal cancer, the authors identify a new mutation in the ectodomain of the receptor. The mutation is present in patient tumors after cetuximab therapy, confirming that it represents a clinically-relevant mechanism for therapy resistance. Moreover, the mutation does not affect the response to other EGFR antibodies, suggesting that if independently confirmed it may be a useful indicator to tailor anti-EGFR therapy.

Congenital disorder of glycosylation-Ia in humans is a multisystemic disease marked by severe neurological deficits and results from deficient glycoprotein processing during development. Christian Körner and his colleagues now show that orally supplying mannose to pregnant dams in a mouse model of the disease is sufficient to ameliorate disease symptoms and early lethality, suggesting a possible therapy to treat this devastating condition.

Spinocerebellar ataxia 1 is a neurodegenerative disease caused by a CAG trinucleotide expansion in the ATXN1 gene encoding the protein ataxin-1. Puneet Opal and his colleagues find that ataxin-1 represses the expression of the angiogenic and neurotrophic factor vascular endothelial growth factor (VEGF) and that VEGF levels are decreased in animals with motor impairment. Overexpression or infusion of VEGF improves motor performance and pathology, suggesting VEGF may have therapeutic potential in this disease.

The placebo response involves a perceived effect of a drug that was not really received by the subject. Fabrizio Benedetti and colleagues demonstrate that the placebo response to NSAIDs in reducing pain is mediated by the endocannabinoid system in humans.

To date, the dogma in the field has been that RANKL, an essential cytokine in osteoclast maturation, is released by osteoblasts as a way to coordinate bone growth and bone loss during adult bone remodeling. Now, Hiroshi Takayanagi and colleagues, as well as Charles O'Brien and colleagues, have independently found that osteocytes are the predominant source of RANKL in the adult mouse. As RANKL signaling is a key target in treating osteoporosis, these results have potentially important implications for disease management.

This report describes the isolation and in vitro expansion of human colon stem cells from normal tissues. Cells with high levels of the membrane receptor EPHB2 are shown to have characteristics of intestinal stem cells, and the authors optimize culture conditions that allow their in vitro expansion as multipotent cells capable of differentiation into several intestinal lineages.