Letters in 2013

A screen for compounds that may inhibit the growth of hematological malignancies reveals the specific dependence of some mantle cell lymphoma (MCL) cell lines on canonical or alternative NF-κB signaling. As also seen in patients, genetic alterations affecting alternative NF-κB signaling confer insensibility to ibrutinib, a compound that was recently approved for MCL treatment. This alternative signaling pathway underscores the need to tailor treatments to the specific driving pathways in each patient group.

Understanding how Mycobacterium tuberculosis is controlled by the body, leading to active disease in only a small fraction of infected individuals, is important for developing medical interventions to prevent and manage disease. Lin et al. now show that infected macaques with active tuberculosis have some sterile granulomas, suggesting immune-mediated control at certain sites of infection. Insight into the mechanisms underlying the heterogeneity of mycobacterial killing may inform vaccine development.

Bao-Liang Song and colleagues report that the clathrin adaptor Numb recognizes a peptide motif within the cholesterol transporter NPC1L1 upon cholesterol binding and thus facilitates dietary cholesterol uptake into the gut. Inhibition of this Numb-NPC1L1 interaction in mice reduces serum cholesterol levels and thus may be a therapeutic target to treat hypercholesterolemia in the clinic.

The suppressive function and number of regulatory T cells (T_reg cells) is reduced in autoimmune disease. Here, Giuseppe Matarese and colleagues report that T_reg cell proliferation is reduced in subjects with relapsing-remitting multiple sclerosis. As disease severity increases, T_reg cell proliferation progressively decreases and is associated with impaired IL-2 release and IL-2 receptor and mTOR signaling.

T cells specific for hepatitis C virus (HCV) have been reported in some individuals who have been repeatedly exposed to virus, yet have never had detectable HCV or HCV-specific antibodies. These findings suggest that T cells in these individuals may protect against infection by HCV. Barbara Rehermann and colleagues now test this assumption in a nonhuman primate study exposing animals to a very low dose of HCV.

Excess ammonia in the blood can cause neurologic dysfunction and seizures. Although previous studies have suggested astrocyte swelling and brain edema are associated with hyperammonemia, the authors show that ammonia compromises potassium buffering by astrocytes, increasing extracellular potassium concentrations and resulting in cortical disinhibition. Pharmacological or genetic inhibition of NKCC1 attenuates ammonia-induced neurologic impairment and seizures, suggesting hyperammonemia may be treated by targeting NKCC1.

Metformin is one of the most widely prescribed therapeutics for type 2 diabetes. But exactly how it works is still unclear. Gregory Steinberg and colleagues now show that it does so by activation of the enzyme AMP-activated protein kinase (Ampk) and Ampk's obligate targeting of two key enzymes involved in lipid homeostasis.

Variation in the promoter of the gene encoding uromodulin, the most abundant protein in urine, affects the individual risk of developing hypertension or chronic kidney disease. Luca Rampoldi, Olivier Devuyst and their colleagues show that the uromodulin risk alleles are associated with higher levels of uromodulin expression. This can promote hypertension, by stimulating sodium reabsorption by the loop of Henle in the kidney, and kidney damage in both mice and humans.

Alteration of the bone marrow microenvironment by activation of the parathyroid hormone receptor attenuates chronic myelogenous leukemia (CML) but enhances acute myeloid leukemia (AML) in mouse models, suggesting that the leukemia stem-cell niches in CML and AML are distinct.

Here, Honegger et al. study two HCV-infected women through two consecutive pregnancies and chronicle T cell escape mutations in viral proteins that revert during pregnancy and reappear postpartum. The findings highlight the dynamic between T cell–mediated pressure and viral fitness, with implications for vertical transmission of HCV.

Dysfunction of the potassium-chloride cotransporter KCC2 has been linked to many neurological diseases, including pain, anxiety and epilepsy. Now, Yves De Koninck and his colleagues report that they have developed a novel small-molecule compound that is orally bioavailable and can activate KCC2 and reduce chronic pain in rats.

This study identifies the concurrent activation of SHH and PI3K signaling by loss of PTEN as a frequent event in glioblastoma tumors that can be targeted with combination treatments using approved drugs to achieve antitumor responses in vivo. The results could potentially lead to the exploration of much needed new combination therapies for human brain tumors.

In two separate studies, Amato Giaccia and Calvin Kuo and colleagues show that targeting of hypoxia-inducible factor-2α to increase its expression results in elevation of a key downstream effector of insulin signaling and thus improved insulin sensitivity in a mouse model of type 2 diabetes.

Patients with hemophilia lacking functional coagulation factor VIII (FVIII) are treated with replacement FVIII proteins. The development of neutralizing antibodies to the replacement FVIII, a major clinical problem, depends on the nature of the mutation in the gene encoding FVIII. The authors find that a prevalent inversion allele can unexpectedly produce FVIII protein, explaining why individuals with this allele do not frequently develop neutralizing antibodies.

In two separate studies, Amato Giaccia and Calvin Kuo and colleagues show that targeting of hypoxia-inducible factor-2α to increase its expression results in elevation of a key downstream effector of insulin signaling and thus improved insulin sensitivity in a mouse model of type 2 diabetes.

The Middle East respiratory syndrome coronavirus (MERS-CoV) has killed ∼50% of individuals known to be infected, making understanding its mechanisms of transmission and pathogenesis and identifying candidate treatments a high priority. Heinz Feldmann, Vincent J. Munster and Michael G. Katze and their colleagues now report that treating MERS-CoV-infected rhesus macaques with interferon-α2b and ribavirin reduced virus replication and infection severity, suggesting the potential use of this combination for the clinical treatment of infected humans.

Thioredoxin-interacting protein (TXNIP) regulates the redox potential of cells and has previously been found to be upregulated in diabetic states. In a new study, Anath Shalev and colleagues show that TXNIP upregulates the expression of miR-204, which in turn downregulates the expression of MAFA, a key transcription factor regulating insulin expression. These results could further explain the progression of diabetes.

The immunosuppressive activity of T regulatory (T_reg) cells has been shown to impair antitumor responses, but depleting these cells has not proved highly promising in the clinic. Wayne Hancock and his colleagues now report that targeting the histone acetyltransferase p300 in T_reg cells is an alternate approach to modulating the function of T_reg cells and show that inhibiting p300 impairs tumor growth without promoting autoimmunity.

Fibroblast growth factor 21 (FGF21) is a cytokine synthesized and released by the liver, muscle and fat and acts both locally and systemically to regulate whole-body metabolism. David Mangelsdorf and his colleagues now show in two separate studies that FGF21 also acts on the region of the brain that regulates circadian rhythm, the suprachiasmatic nucleus, to further regulate whole-body metabolism as well as reproductive function.

Fibroblast growth factor 21 (FGF21) is a cytokine synthesized and released by the liver, muscle and fat and acts both locally and systemically to regulate whole-body metabolism. David Mangelsdorf and his colleagues now show in two separate studies that FGF21 also acts on the region of the brain that regulates circadian rhythm, the suprachiasmatic nucleus, to further regulate whole-body metabolism as well as reproductive function.