Letters in 2010

The antithrombotic drug clopidogrel, widely prescribed after heart attacks, is a prodrug and must be metabolically activated. The efficiency of this activation step varies among individuals and is thought to account for clopidogrel's variable clinical efficacy, a major drawback to its use. Heleen Bouman et al. provide biochemical, clinical and epidemiological evidence to show that a common polymorphism in the gene encoding paraoxonase-1 is largely responsible for this variability. Paraoxonase-1 genotyping might identify those individuals unlikely to benefit from clopidogrel treatment.

Adenovirus type 37 (Ad37) causes epidemic keratoconjunctivitis, a highly contagious disease for which there is no specific antiviral therapy. The receptor for Ad37 infection was previously unidentified, but known to contain sialic acid. Nilsson et al. report here that Ad37 binds to the GD1a glycan motif of the GD1a ganglioside. This finding may facilitate the development of antiviral agents targeting Ad37-associated disease.

Proteinuria results from defects in glomerular filtration, often as a result of kidney injury or inflammation. Sumant Chugh and his colleagues now show that the glycoprotein Angptl4 is highly upregulated in minimal change disease, a type of human proteinuria, and that genetic deletion protects against experimentally induced proteinuria in mice.

Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. A serum antibody preexisting in middle-aged adults cross-reacts with, but does not protect against, 2009 H1N1 influenza virus. The existence of this antibody may account for the unusual age distribution of severe flu cases during pandemics.

Brain injury after stroke requires glutamate receptor activation of neuronal nitric oxide synthase (nNOS), but inhibiting either of these proteins can cause side effects. Now, Dong-Ya Zhu and colleagues show that a drug that blocks the interaction between nNOS and a glutamate receptor docking protein can reduce stroke damage in vivo, with no observed side effects.

By acting on the P2X₇ receptor, ATP released upon cell damage functions as a danger signal to promote acute graft-versus-host disease after bone marrow transplantation in mice.

The authors characterize a previously undescribed function of Snf5 that involves interaction with the transcription factor Gli1 and downregulation of its activity via chromatin remodeling. Snf5 is shown to restrict Hedgehog (Hh) signaling in normal development and cancer. Hh inhibition emerges as a potential therapeutic strategy for malignant rhabdoid tumors in which Snf5 is commonly lost.

Gene expression changes that occur in the brains of people with depression could lead to the development of new therapies. Now, Ronald Duman and his colleagues report that the phosphatase Mkp-1 is upregulated in the postmortem hippocampus of individuals with depression, and altering the expression of this protein in rats and mice can regulate depressive behaviors and their resistance to stress.

The inhibitory receptor programmed death-1 (PD-1) is upregulated on exhausted CD8⁺ T cells in HIV-infected individuals. Quigley et al. analyzed the transcriptional profile induced by PD-1 ligation and report that a transcription factor, BATF, is upregulated by PD-1 signaling and has a key role in PD-1–mediated inhibition of T cell function.

Migraine headaches are a debilitating condition that affect many individuals. Now, Guy Rouleau and his colleagues link loss-of-function mutations in a potassium channel protein with a particular migraine syndrome in humans.

For bone marrow transplantation, donor hematopoietic cells are routinely mobilized from the bone marrow to the peripheral blood by the cytokine G-CSF. By studying mouse strains that respond to G-CSF with varying degrees of mobilization, Marnie A. Ryan et al. discovered that the epidermal growth factor receptor, acting in bone marrow cells, restrains this response. An inhibitor of epidermal growth factor receptor activity augmented G-CSF–induced mobilization in mice, suggesting that this approach might be clinically useful in bone marrow transplantation.

The body typically responds to its environment in a rhythmic, or circadian, fashion, including endogenous hepatic glucose production (HGP)—a key response to fasting. Steve Kay and his colleagues have now found that important mediators of the circadian clock in the liver also regulate HGP and that their genetic overexpression improve glucose metabolism and insulin sensitivity in a mouse model of type 2 diabetes.

Recent studies have shown that neutrophil extracellular traps (NETs) can capture and kill bacteria but may also contribute to chronic inflammation. The mechanisms that trigger NET formation are not yet fully elucidated. Marcos et al. now report that stimulation of the chemokine receptor CXCR, induces NET formation and that NETs are present in airway fluids of individuals with cystic fibrosis. Blocking CXCR2 activation in the lung reduced NET formation and improved lung function in a mouse model of cystic fibrosis.

ALDH-2 inhibitors are a potential treatment for alcohol addiction. Now, Lina Yao et al. show that ALDH-2 inhibitors can reduce addiction to cocaine in rats by generating a dopamine metabolite called THP. THP inhibits an enzyme involved in dopamine synthesis, thereby blocking dopamine production in response to cocaine.

Sudarshan Anand et al. show that endothelial cell expression of the microRNA miR-132 targets a negative regulator of Ras pathway signaling and thereby releases a brake to new blood vessel formation. miR-132 expression is upregulated in the endothelium of human hemangioma and tumor samples, and an antagonist of miR-132, delivered specifically to tumor endothelium using an integrin-targeted nanoparticle, was able to inhibit tumor angiogenesis and growth in mice.

During pregnancy, women often become insulin resistant, thus requiring an expansion of pancreatic beta cell mass to provide more insulin. Michael German and his colleagues now report that lactogenic hormones drive the expression of serotonin in the beta cells to induce this increase in beta cell mass.

Glycosphingolipid modulation may be a new approach to treat polycystic kidney disease. Blocking glucosylceramide accumulation with a glucosylceramide synthase inhibitor inhibits cyst formation in mouse models of the disease through inhibition of Akt-mediated signaling and by interfering with the cell cycle machinery.

Using pair-end transcriptome sequencing, this study provides the identification of Raf pathway gene rearrangements in a small proportion of prostate and gastric cancers and in melanomas. The fusion proteins show tumorigenic potential and represent a unique activating alteration of this oncogenic pathway, which seems to be mutually exclusive from known cancer-associated Raf mutations. This suggests that therapeutic Raf inhibition can be expanded to this fusion-harboring subset of solid tumors.

Immunologically targeting α-lactalbumin, a breast-specific protein highly expressed in breast carcinomas but absent from nonlactating mammary cells, provides protection against breast cancer in mice. This strategy may protect women against breast cancer in their post–child-bearing years, when lactation is readily avoidable and risk for developing breast cancer is high.

The treatment options for sepsis are limited in scope and efficacy, resulting in frequent human fatalities. Liew and colleagues now report that interleukin-33 is a promising therapeutic strategy that increases neutrophil recruitment to the site of infection and bacterial clearance and decreases mortality in a mouse model of sepsis.