Volume 18 Issue 9, September 2012

By 2014, the UK will be changing the way it regulates the price it pays for medicines. The government has embraced an idea known as value-based pricing (VBP), with negotiations on how the system will work due to begin this month. One of the most influential thinkers on the UK’s proposed system is health economist Mark Sculpher, director of the Programme on Economic Evaluation and Health Technology Assessment at the University of York. Kate Ravilious met with Sculpher to discuss the value of VBP.

The idea of using bacteria-fighting viruses as a weapon against hard-to-treat infections is making a surprising comeback, but with a twist on how it has been attempted for nearly a century. Researchers and companies are now tweaking and deconstructing these bacteria killers in an effort to develop a new arsenal against antibiotic-resistant superbugs—one with more potency and a better likelihood of regulatory approval. Lauren Gravitz reports.

Doctors and regulatory agencies rely on meta-analyses when setting clinical guidelines and making decisions about drugs. However, as the number of these analyses increases, it's clear that many of them lack robust evidence from randomized trials, which may lead to the adoption of treatment modalities of ambiguous value. Without a more disciplined approach requiring a reasonable minimum amount of data, meta-analyses could lose credibility.

Hepatic fibrosis results from chronic liver injury due to viral infection, metabolic diseases, toxins such as alcohol, or immune attack. Now, a heritable epigenetic determinant of fibrosis has been uncovered, providing evidence that sperm from male rats with liver injury confers reduced fibrosis in their male offspring (pages 1369– 1377).

A better understanding of mechanisms involved in regulation of drug sensitivity is crucial for improved cancer treatment. New studies show that cells of the tumor microenvironment modulate the response of cancer cells to chemotherapy and targeted therapies through production of secreted factors (pages 1359–1368).

Unraveling the intracellular networks that regulate the self-renewal and differentiation of hematopoietic stem cells (HSCs) is crucial to enhancing the efficacy of these therapeutic transplantable cells. A newly discovered pathway links a leukemia tumor suppressor gene with a nutrient sensor to regulate fatty-acid oxidation (FAO) and stem cell division—information with the potential for modulating hematopoiesis for clinical advantage (pages 1350–1358).

Neutrophils release extracellular DNA traps (NETs) to capture and kill pathogens. A recent study shows that live neutrophils are simultaneously able to form NETs while crawling and phagocytosing and can even combat bacteria after loss of their nuclear DNA (pages 1386–1393).

T cells responding to tumor cells and chronic viral pathogens are ineffective because their function is suppressed by inhibitory receptors such as Tim-3. New work identifies the first component of the Tim-3 inhibitory signaling pathway in T cells (pages 1394–1400).

Complement is intricately involved in inflammatory processes, yet the mechanisms that modulate the actions of its key mediator C5a are poorly understood. A new study uncovers a molecular partnership between three neutrophil receptors in the recognition of differentially glycated immune complexes and sheds light on regulatory processes in autoimmune and inflammatory disorders (pages 1401–1406).

Formation of plaques in artery walls, or atherogenesis, is known to lead to cardiovascular disease risk and heart disease. Low-density lipoproteins (LDLs), which deliver cholesterol to inflammatory cells in blood vessels, are linked to disease, which is commonly managed using cholesterol-lowering therapies. Whether increasing levels of high-density lipoproteins (HDLs), which remove cholesterol from the circulation, can be cardioprotective has not been clear, despite early clinical studies showing evidence for a positive effect in cardiovascular disease. In 'Bench to Bedside', Daniel J. Rader and Alan R. Tall discuss how the field should focus on promoting reverse cholesterol transport that would result in cholesterol efflux from macrophages to biliary excretion rather than simply trying to increase HDL cholesterol levels. Understanding how different molecular mechanisms operate in this 'HDL flux hypothesis' will uncover ways to develop HDL-targeted therapeutics that will protect from cardiovascular and heart disease. In 'Bedside to Bench', Jay W. Heinecke peruses clinical studies to propose better and simpler ways to measure reverse cholesterol transport in the clinic. Genetic alterations and factors involved in HDL functionality may be useful for quantifying HDL function and finding effective drugs to lower cardiovascular disease risk.

Keisuke Ito et al. uncover a new pathway regulating hematopoietic stem cell maintenance and function. In this pathway, the promyelocytic leukemia protein (PML) regulates the activity of the PPAR-δ nuclear hormone receptor and, thereby, fatty acid oxidation, such that PPAR-δ activators have the potential of improving stem cell function. Intriguingly, this pathway controls the cell fate of dividing stem cells.

Responses to anticancer therapy are hampered by several factors, and Peter S. Nelson and colleagues here identify a protective effect of the tumor microenvironment. After cytotoxic chemotherapy, inflammatory NF-κB signaling activates the secretion of WNT16B, which acts on epithelial cells, promoting their survival and fostering tumor growth in vivo. This pathway is also active in human tumors treated with chemotherapy and illustrates the potential caveats of cyclical therapy and the need to overcome environmental protection to successfully eliminate tumors.

Derek Mann and his colleagues have found that experimental induction of liver fibrosis in male rats results in an epigenetic modification of the chromatin in their sperm such that their offspring have a more mild wound-healing response to hepatic fibrogenic insults. The mechanism responsible for this phenomenon is not clear, but it seems to involve a yet unidentified soluble factor released by myofibroblasts that act on either the germ cells or mature sperm.

Highly active antiretroviral therapy is crucial to controlling the progression of HIV infection. Therapy failure is often—but not always—attributed to resistance mutations in the HIV-1–encoded protein targets. Here Rosenbloom et al. use mathematical modeling to explain the distinct patterns of resistance found with different classes of antiretroviral drugs and predict specific single-pill combination therapies that might prevent resistance even in the setting of poor patient adherence.

Bacteria can be trapped by neutrophil extracellular traps (NETs) in vitro, but their relevance in vivo is uncertain, in part because NETs are thought to be released by dying neutrophils, thereby eliminating the other antimicrobial functions of these cells. Paul Kubes and his colleagues report in this issue that NET release need not kill neutrophils and that NETosis can by dynamically imaged in vivo.

T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells and suppresses T helper type 1 (T_H1) responses. Vijay Kuchroo and his colleagues show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds intracellularly to Tim-3 and represses its function. Bat3 knockdown suppresses the development of experimental autoimmune encephalomyelitis and induces an exhaustion-like phenotype in T cells.

Complement components activate and recruit immune cells, promoting host defense and inflammatory disease. Jörg Köhl and his colleagues demonstrate that IgG1 immune complexes inhibit C5a-mediated inflammatory responses and disease. The inhibitory effect of IgG1 immune complexes requires galactosylation of the antibody, binding to the inhibitory IgG receptor FcγRIIB and the association of FcγRIIB with the C-type lectin–like receptor dectin-1.

Infiltration of various immune cell types into the fat tissue and liver has been implicated in obesity-induced insulin resistance. Jerry Olefsky and his colleagues now show that neutrophils are one of the earliest immune cells to arrive in these tissues, that they release the protease neutrophil elastase and that this enzyme degrades IRS-1, a key member of the insulin signaling pathway. These results show that neutrophils contribute to insulin resistance and how they may do so.

Ronald Duman and colleagues report that synapse number is reduced in subjects with major depressive disorder. This is associated with decreased expression of synapse-related genes and increased expression of the transcriptional repressor, GATA1. Expression of GATA1 in prefrontal cortex neurons decreases the expression of synapse-related genes, reduces dendrite branching and produces depressive behavior in a rat model of depression.

Epha4 is a receptor involved in axonal repulsion. Wim Robberecht and his colleagues report that genetic or pharmacological inhibition of Epha4 is protective in rodent and zebrafish models of amyotrophic lateral sclerosis. In humans, expression of Epha4 inversely correlates with disease onset and survival, and in two patients, mutations in Epha4 are associated with longer survival, suggesting Epha4 may be targeted therapeutically to prevent axonal degeneration.

Ciliopathies are caused by alterations in the development and function of cilia. Now Jeffrey Martens and his colleagues demonstrate anatomic and functional rescue of cilia development in mature, differentiated neurons by adenovirus-mediated restoration of expression of the wild-type protein intraflagellar transport protein 88 (Ift88) and show restoration of olfactory function in a mouse model of ciliopathy. A loss-of-function mutation in IFT88 is also identified in individuals with ciliopathies.

The mineralocorticoid receptor, targeted by drugs commonly used to treat hypertension, is generally thought to contribute to hypertension by altering kidney function. Using mice lacking the mineralocorticoid receptor specifically in smooth muscle cells, Iris Jaffe and her colleagues show that it also controls many aspects of vascular aging, including blood vessel tone, and that these vascular effects contribute to the mineralocorticoid receptor's prohypertensive actions.

Using the semiconductor synthesis technology of maskless photolithography on microprocessor-grade silicon wafers, Jordan Price and colleagues synthesized microarrays containing every possible overlapping peptide in a linear sequence covering the N terminus of human histone H2B, including post-translational modifications. They demonstrated use of the 'on silico' peptide microarrays for the high-resolution mapping (at the single amino acid level) of epitopes targeted by commercially available H2B-specific antibodies and also by autoantibodies in samples from individuals with systemic lupus erythematosus.