Volume 20 Issue 5, May 2014

 Last month, Genentech entered a five-year partnership with PatientsLikeMe to mine the online patient network’s database of real-world experiences from more than 250,000 members with 2,000 different conditions. At the helm of PatientsLikeMe is Jamie Heywood, a mechanical engineer by training who devised the idea for the platform ten years ago when he noticed some striking similarities between the information asked of online dating websites and clinical trial portals. Nicholette Zeliadt spoke to Heywood about what this new partnership will mean for open-participation research.

Patients have long received cancer treatments at the maximum tolerated dose on a regular schedule. Could a more sophisticated approach save lives? Elie Dolgin meets one mathematical biologist whose theories are now being tested in the clinic to see if they can improve the efficacy of today's anticancer arsenal.

The function of the innate immune system is suppressed in patients with acutely decompensated cirrhosis and predisposes these patients to bacterial infections. A new study shows that increased synthesis of the immunosuppressive prostaglandin PGE₂ by circulating monocytes and resident macrophages and impaired hepatic synthesis of human serum albumin (HSA) are major contributors to immune suppression in cirrhosis (pages 518–523). The authors' data suggests a new avenue for therapy in acute decompensation of cirrhosis.

As babies leave their mothers' wombs, they are colonized by commensal bacteria. A new study shows that these microbes in a newborn's gut can promote an increase in circulating neutrophils that can guard the body from infections. Altering a neonate's gut microbiota with perinatal antibiotic treatment can impair neutrophils, leaving the newborn vulnerable to attack by harmful bacteria (pages 524–530).

A new antiviral capacity for matrix metalloproteinase 12 (MMP-12) adds to our expanding understanding of matrix metalloproteinase biology, from matrix remodeling to host defense, in this issue of Nature Medicine (pages 493–502). Marchant et al. show that following viral infection, macrophages secrete MMP-12, which regulates antiviral immunity both as a transcription factor for IκBα, leading to interferon-α (IFN-α) secretion, and later by degrading extracellular IFN-α, resolving inflammation.

Central nervous system (CNS) control of systemic nutrient homeostasis is a crucial but poorly understood metabolic regulatory axis. A new study (484–492) shows that rat insulin promoter (RIP)-expressing neurons in the hypothalamus regulate peripheral metabolic responses to both normal and high-fat diets through anti-inflammatory effects mediated by vagal innervation of the spleen.

DNA that is shed by dead tumor cells into the blood, termed circulating tumor DNA (ctDNA), is a rich resource that could potentially be used for cancer diagnostics and monitoring. A new study describes a sequencing-based method that improves upon the sensitivity and specificity achieved by past techniques for detecting ctDNA and that can be used for monitoring of disease burden in patients with non–small-cell lung cancer (pages 548–554).

The challenges posed by the biology of the virus remain a barrier to obtaining a complete cure using current antivirals and to developing a working vaccine that will protect from infection and clear disease. Researchers are keenly working to uncover how to elicit long-term broadly neutralizing antibody responses in humans that will protect against infection from all HIV clades and to ensure that people already infected will also have a chance at clearing the virus and being cured. In “Bedside to Bench,” Florian Klein and Henning Gruell discuss a recent study that tracked how broadly neutralizing antibodies developed in an HIV-infected individual during the natural course of the disease. The findings will help create a roadmap to identify the necessary steps to induce antibody maturation for achieving a broad and potent protective humoral response. Another important aspect that defies HIV eradication in infected individuals is the existence of viral reservoirs that allow the virus to hide from antiviral killing. In “Bench to Bedside,” Robert Siliciano peruses recent advances in animal models providing evidence that eliciting effector memory cellular responses to HIV may help eradicate—or prevent the establishment of—latent reservoirs. This strategy could contribute to clearing HIV in treated infected individuals and add to the protection of a humoral vaccine response.

A new study by Minna Woo and colleagues shows that a neuronal relay from the brain to the adipose tissue regulates whole-body insulin sensitivity by affecting macrophage function, and thus inflammation, in the periphery. These results suggest that a centrally mediated anti-inflammatory reflex exists to regulate metabolic health.

Matrix metalloproteinases (MMPs) normally act extracellularly. Now Marchant et al. report an unexpected nuclear activity for MMP-12 in virus-infected cells in regulating transcription of the gene encoding IκBα and affecting secretion of interferon-α.

The maintenance of memory B cells is essential for vaccines to protect against infection. In this issue, Jin Wang and colleagues report that autophagy is required to maintain mouse memory B cells and that mice deficient for autophagy have normal primary antibody responses but impaired secondary responses to an influenza vaccine, resulting in their susceptibility to influenza virus infection.

Neutrophil extracellular traps (NETs) are released by neutrophils in response to infection and have also been observed in sterile inflammation. Here, monosodium urate crystals, found in gout, are shown to induce NET formation and aggregation. These aggregated NETs proteolytically degrade cytokines and chemokines and reduce inflammatory responses. NETosis-deficient mice develop chronic inflammatory disease that can be attenuated after the transfer of aggregated NETs, suggesting that the formation of aggregated NETs may serve to limit inflammation.

Patients with cirrhosis are susceptible to infection, but the mechanisms underlying this immunosuppression remain unclear. Derek W. Gilroy and colleagues show that plasma prostaglandin E₂ (PGE₂) is elevated in these patients and in mouse models of liver injury and suppresses TNF-α release from macrophages. Albumin, which binds to PGE₂ and reduces its bioavailability, is reduced in the plasma of a subset of cirrhosis patients. Administration of albumin partially reverses the immunosuppression observed in vitro and restores bacterial killing in mouse models, suggesting that future studies are warranted on the use of albumin to prevent infection in a subset of patients with cirrhosis.

Here, Hitesh S. Deshmukh et al. report that in neonates, establishment of the intestinal microbiota is associated with neutrophil development. Antibiotic-treated and germ-free mice have reduced numbers of neutrophils and are susceptible to Escherichia coli K1 and Klebsiella pneumoniae sepsis. Reconstitution of the intestinal microbiota promotes interleukin-17 production by innate lymphoid cells and increases plasma granulocyte colony–stimulating factor levels, granulocytosis and host resistance to sepsis.

Chronic stress can lead to depression. Ronald Duman and his colleagues show that REDD1 expression is increased in the brain of patients with major depressive disorder and is upregulated in the brains of stressed mice. Mice lacking REDD1 were resistant to stress-induced depressive behaviors, and unstressed rats in which REDD1 was artificially increased exhibited depressive behaviors.

A potential treatment for Huntington's disease involves reducing expression of the mutant gene, but it is unclear to which part of the brain the treatment should be directed. Now, X. William Yang and colleagues show that reducing HTT expression in both the striatum and the cortex provides the most benefit for ameliorating disease in mice when compared with reducing expression in just one of the two brain structures.

In Friedreich's ataxia, caused by mutation of the gene encoding the mitochondrial protein frataxin, the major cause of mortality is heart failure. Using mice lacking frataxin in the heart, Hélène Puccio and her colleagues demonstrate that frataxin gene therapy can correct mitochondrial metabolism and reverse heart damage, raising the possibility of a gene therapy treatment for this disease.

Aaron Newman and his colleagues introduce a next-generation sequencing–based approach for the cost-effective detection and quantitation of tumor-derived circulating DNA in both early- and advanced-stage tumors and with high levels of sensitivity and specificity. CAPP-Seq (cancer personalized profiling by deep sequencing) can simultaneously detect multiple mutations and mutation types, including rearrangements. Here, utility is demonstrated for non–small-cell lung cancer.

Michael Breckwoldt and colleagues have developed a new approach to follow the mitochondrial redox potential of neurons with high spatio-temporal resolution. This multiparametric in vivo imaging approach is based on the transgenic expression of a biosensor for glutathione redox potential in neuronal mitochondria, with utility demonstrated in mouse models of amyotrophic lateral sclerosis and spinal cord injury. It should prove useful for studying mitochondrial pathology in neurological disease models.