Volume 19 Issue 10, October 2013

Thanks to the automatic cuts in US government spending, the approximately $9-million-per-year contract the Framingham Heart Study receives from the US National Heart, Lung, and Blood Institute was reduced by $4 million on 1 August. Overseeing the budget-related turbulence is Daniel Levy, a medical officer at the NHLBI who joined the FHS nearly 30 years ago and has served as the study's director since 1994. Elie Dolgin met with Levy to discuss how he's taking the new funding realities to heart.

Discovering the right compound that can treat an infection such as HIV is only the first piece of the drug development puzzle. The next challenge is to make the manufacturing process more efficient—and thereby cheaper. Killugudi Jayaraman meets with the 'process chemistry' experts honing these reactions to bring down the cost of antiretrovirals.

Drug development depends on preclinical experimentation in animal models. To make the public aware of the vital role of these studies, pharmaceutical companies should be legally obliged to make note of this on their products that came to fruition through animal research.

Glioblastoma multiforme (GBM) is the most common type of aggressive malignant brain cancer. The current lack of successful therapeutics means that this disease has a dismal prognosis. However, a new study in mice offers hope for patients with GBM by demonstrating the efficacy of a novel drug that targets GBM-associated macrophages (pages 1264–1272).

After myocardial infarction (MI), circulating B cells produce the chemokine Ccl7, which mobilizes inflammatory monocytes from the bone marrow into the blood, after which they are then recruited to the injured heart, a new study shows. B cell depletion after MI limits myocardial injury and improves heart function, suggesting a new approach for the management of acute MI (pages 1273–1280).

Aspergillus fumigatus is a fungus that is associated with a severe form of asthma, although the precise immunological basis for this disease is unclear. A new study in mice shows that natural killer T (NKT) cells are crucial for progression of A. fumigatus–induced asthma and also identifies a glycolipid antigen from this fungus that seems to drive this NKT cell–mediated inflammatory response (pages 1297–1304).

A signaling cascade is activated in podocytes to induce survival and cope with stress during advanced glomerular disease, a new study shows. The findings may also explain why the immunosuppressor sirolimus, an inhibitor of this pathway, can cause proteinuria in a subset of patients with chronic kidney disease (pages 1288–1296).

Given the multisystemic nature of the metabolic syndrome, the field is now aiming at perusing both intrinsic and environmental factors from a biological and therapeutic standpoint. Physicians often advise obese individuals suffering from type 2 diabetes to lose weight through exercise and healthy diets. Although it may be an obvious recommendation, a large study has recently shown that weight loss achieved through these lifestyle changes does not significantly reduce cardiovascular disease events in these patients compared to conventional diabetes care. In 'Bedside to Bench', Julie A. Lovshin and Daniel J. Drucker discuss the limitations of this study, the conclusions that can be drawn regarding the true benefit of weight loss in this context and the molecular factors that deserve further attention at the bench in light of this trial. In 'Bench to Bedside', Eleftheria Maratos-Flier examines the role of antidiabetic drugs in both host and gut microbiota metabolism. These effects in the intestinal flora support advocating an increase in our understanding of how the gut microbiome affects obesity for finding the means to harness its therapeutic potential.

Bill and Melinda Gates have led a profound transformation in the way we view the world's most pressing health concerns, looking for effective ways to improve the lives of millions of people. Claire Pomeroy, president of the Albert and Mary Lasker Foundation, spoke with them about their current concerns and plans to advance their agenda.

There is much interest in brown and beige adipocytes, as their thermogenic activities can suppress weight gain and metabolic disease in rodent models. The authors review recent data that have provided new insights into the development and biology of brown and beige adipocytes and critically assess the possibilities for manipulating these cells to combat obesity and its associated diseases.

The authors provide preclinical testing of a CSFR-1 inhibitor in proneural glioma models. The compound targets macrophages in the tumor microenvironment rather than tumor cells themselves and is shown to portend considerable antitumor effects. Its activity relies on re-education of tumor-associated macrophages without affecting their survival, reverting their tumor-promoting phenotype. Moreover, gene signatures capturing the tumorigenic features of macrophages can predict survival in human patients with glioma, underscoring the potential relevance of this strategy as a glioma therapy.

After myocardial infarction, inflammatory cells are rapidly recruited to the heart and strongly affect the course of recovery. Ziad Mallat and his colleagues uncover a pathogenic role for B cells after myocardial infarction, showing that infarction triggers B cell secretion of the chemokine Ccl7, which mobilizes monocytes from the bone marrow, increases their recruitment to the heart and impairs heart function.

In the process of autophagy, cellular constituents are degraded and recycled. Toren Finkel and his colleagues show that this process also regulates the secretion of a key blood-clotting protein by endothelial cells, such that transient inhibition of autophagy might be therapeutically useful for treating thrombotic disorders.

Rapamycin (also known as sirolimus) is a potent immunosuppressive drug that is often used after organ transplant to prevent rejection, but it also can cause kidney dysfunction. Fabiola Terzi and her colleagues now show this side effect of rapamycin is due to targeting of mTORC2 and suppression of AKT2 activity in podocytes. They also show that AKT2 normally acts to maintain podocyte viability and structure during chronic kidney disease.

Sensitization to the fungus Aspergillus fumigatus is associated with allergic airway disease and asthma. Now Dale Umetsu and colleagues report that invariant natural killer T (iNKT) cells directly recognize the glycosphingolipid asperamide B derived from A. fumigatus. Asperamide B stains and activates mouse and human iNKT cells and induces airway hyper-reactivity in mice, suggesting that fungi can be directly detected by iNKT cells.

The correlates of protection against illness caused by natural influenza infection in seronegative individuals is important for the design of vaccines capable of conferring immunity against different influenza virus strains. Sridhar et al. now report their analysis of individuals infected by the 2009 H1N1 pandemic influenza virus and show that the presence of pre-existing CD8+ T cell responses to conserved influenza epitopes is associated with reduced severity of illness. The findings support the importance of developing universal influenza vaccines that are capable of inducing crossreactive T cell responses to mitigate influenza illness.

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.

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.

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.

Qiong Wang and colleagues introduce the AdipoChaser mouse, an in vivo tool to track the formation and turnover of adipocytes. They use this inducible mature adipocyte lineage-tracing system to monitor adipogenesis and follow the formation of white and beige adipocytes under different conditions: high-fat diet, cold exposure and β-adrenergic stimulation. The system produced some interesting findings on in vivo adipogenesis, including that beige adipocytes differentiate de novo from specialized precursors rather than by transdifferentiation of mature white adipocytes.

Thorek et al. describe an activatable imaging agent based on a radioactive decay signal through the Cerenkov luminescence effect, which is light produced by β-particle–emitting radionuclides, such as clinically available PET tracers. The approach offers a means of simultaneously investigating multiple disease-relevant biological activities in vivo—the radioluminescent readout providing a quantitative measure of enzymatic activation with reduced background.