Volume 18 Issue 8, August 2012

With a budget of $3.3 billion over the next seven years and an independent status, the Patient-Centered Outcomes Research Institute (PCORI) is tasked with creating the evidence base to help patients and doctors make more informed decisions about their medical choices. Elie Dolgin spoke with PCORI executive director Joe Selby, a family physician and clinical epidemiologist who joined the institute after 13 years as head of research at Kaiser Permanente, the California-based health provider.

When it comes to clinical trials, physicians almost always run the show. But a determined group of nurses is taking the reins, which some hope will lead to improved patient recruitment, particularly in women's health. Rebecca Hersher looks into whether the nurse is the principal investigator of the future.

The compulsory license mechanism is broken and will not bring drug access to the world's poorest nations. It's time to consider another option—a tax levied on patents—to fund drugs for developing countries, rather than the erratic compulsory licensing mechanism.

Malignant gliomas are devastating, uniformly fatal cancers for which current therapies remain palliative. A new study in mice shows that neural precursor cells, abundant in neonatal brains, release a fatty acid factor that induces glioma cell death through the activation of TRPV1 channels, prolonging survival and potentially uncovering a new treatment strategy (pages 1232–1238).

There is currently much interest in dissecting the mechanisms of tumor immunity. A new study shows that a subset of CD4⁺ T cells that produce the cytokine interleukin-9 (IL-9) mediate inhibition of melanoma growth in mice and that analogous IL-9–producing T cells are present in human skin (pages 1248–1253). Could such cells be manipulated to develop new therapeutic strategies for melanoma?

Fibrosis is omnipresent and contributes to a substantial proportion of all natural deaths. A recent study (pages 1262–1270) provides evidence that the mysterious perivascular cell, also known as the pericyte, is the cell type responsible for fibrotic disease in skin and skeletal muscle.

Prolonged febrile seizures in young children have long been suspected to lead to temporal lobe epilepsy, but how this occurs has been unclear. A new study (pages 1271–1278) in rats showing that febrile seizures induce aberrant migration of cells in the temporal lobe suggests this may be a crucial component in the development of epilepsy.

The liver secretory protein fetuin-A (FetA) is now shown to act as an adaptor protein between free fatty acids (FFAs) and Toll-like receptor 4 (TLR4), providing the missing link between FFAs and chronic low-grade inflammation that impairs insulin sensitivity (pages 1279–1285).

A new mechanism regulating pathological angiogenesis has been identified that involves the activation of ataxia-telangiectasia mutated (Atm) kinase in response to reactive oxygen species. Importantly, this Atm-dependent pathway is specifically activated in pathological, but not in normal, angiogenesis, suggesting that it could be therapeutically targeted in diseases associated with pathological angiogenesis (pages 1208–1216).

Millions of healthy bacteria colonize our guts from the moment we are born. Changes in the composition and abundance of these commensals affect the entire immune system and can predispose us to a variety of diseases, including intestinal infections, inflammatory and metabolic diseases, and cancer. The gut microbiome interacts not only with the host mucosa but also with potential pathogens; understanding what interactions and pathways are crucial for maintaining homeostasis and protecting the host from harmful bacteria and diseases can open new avenues to developing gut microbiota–based therapeutic approaches. In 'Bench to Bedside', Michael R. Howitt and Wendy S. Garrett examine the importance of metabolic crosstalk between the microbiota and the host in human metabolism and the development of cardiovascular disease. This adds one more layer of complexity to understanding what contributes to this pathology and how to harness the microbiota and their metabolic pathways to prevent it. In 'Bedside to Bench', Nobuhiko Kamada, Grace Chen and Gabriel Núñez discuss how targeting interactions between commensals and bacteria causing intestinal disease can lead to effective therapies to control these infections, which currently seem to lack an adequate treatment. Unraveling how commensals help the host prevent or block colonization of these pathogens can suggest new ways to increase our armamentarium to deal with these sometimes deadly intestinal infections.

This review describes how the evolving field of neuroepigenetics can provide a new understanding of the mechanisms involved in neurodevelopmental and neurodegenerative disorders. It also discusses how epigenetic therapeutics that have been approved for other diseases, such as cancer, could be useful in modulating neurological conditions associated with epigenetic abnormalities.

A slight mechanical pressure applied to healthy skin results in blood vessel dilation, preserving blood flow. Defects in this vasodilatory response lead to an increased risk of pressure ulcers. Fromy et al. identify the neuronal mechanosensor that mediates this response in both rodents and humans: the ion channel Asic3.

Yuji Okuno et al. find that pathological angiogenesis in mice requires dampening of oxidative stress. In the absence of the ATM protein kinase, increased oxidative stress leads to activation of the p38α protein kinase and inhibition of new blood vessel growth. These findings run counter to the commonly held concept that decreasing oxidative stress would inhibit pathological angiogenesis and suggest new targets for treating diseases involving abnormal blood vessel growth.

The glycocalyx is a layer of proteoglycans and complex carbohydrates that lines the endothelial cell surface in blood vessels. Schmidt et al. show that in mouse models of sepsis, lung inflammation and injury depend on glycocalyx degradation, which increases neutrophil access to endothelial adhesion molecules. The authors also provide data indicating the potential relevance of this mechanism of lung injury to humans with sepsis.

The authors identify Irf7 and associated interferon signaling as an important factor suppressing bone metastasis of breast cancers. Irf7 is lost in experimental metastasis and human bone metastastic tissue, and this fosters an immunosuppressive environment that facilitates metastasis. Manipulating this innate immune signaling pathway emerging from tumor cells by interferon administration had beneficial effects in mouse models by reducing bone metastasis and increasing survival time.

The authors uncover a mechanism for the known antitumor effect exerted by neural precursor cells (NPCs). NPCs migrate into tumors in vivo and secrete endovanilloids, which act as agonists for TRPV1, their receptor expressed by glioma cells. TRPV1 activation causes ER stress and glioma cell death. The reported elevated concentration of TRPV1 in human gliomas and the antitumor effect of synthetic vanilloids suggest that this pathway could be a point of therapeutic intervention and that differential NPC activity, such as that modulated by age, could be a factor influencing brain tumorigenesis.

Although loss-of-function p53 alterations are widespread in many tumors, melanomas typically do not harbor TP53 mutations. This report uncovers upregulation of MDM4 as a frequent trait of melanomas that contributes to tumorigenesis by inactivating p53 signaling. MDM4 is required for growth and survival of melanoma cell lines, and compounds that can target MDM4 are effective against melanoma in vivo and against tumors resistant to BRAF-targeted therapy in vitro.

In this issue, Thomas Kupper and colleagues report that mice deficient for ROR-γ or interleukin-23 (IL-23) receptor showed impaired melanoma growth. Tumor growth inhibition was dependent in part on IL-9 and T helper type 9 (T_H9) cells. Moreover, the authors showed that IL-9 acts on mast cells rather than T or B cells to mediate its antitumor effects and that T_H9 cells are present in human blood and skin, suggesting that a role for T_H9 cells in human tumor immunity should be explored.

In this issue, Walter et al. report the results of two clinical trials of a new therapeutic vaccine, IMA901, for the treatment of renal cell carcinoma (RCC). IMA901 consists of ten tumor-associated peptides identified as naturally presented T cell epitopes in RCC, and the authors show longer overall survival in subjects with immune responses to multiple vaccine peptides and identify serum and cellular biomarkers that may help predict overall survival in future studies of the vaccine.

Organ fibrosis often leads to end-stage organ failure, but the origin of key profibrotic cell types is still unclear. Lucie Peduto and her colleagues have used genetic lineage tracing and pharmacological ablation techniques to show that ADAM12⁺ perivascular cells are a key source of profibrotic cells in acute skin and muscle injury in the mouse. They also show that knockdown of ADAM12 expression is beneficial, suggesting a possible therapeutic target for the treatment of fibrosis.

Febrile seizures during childhood are linked to the development of chronic epilepsy. Now, Ryuta Koyama and colleagues show that febrile seizures are associated with enhanced GABAergic excitation and ectopic granule cell migration in the hippocampus.

Excess free fatty acids (FFAs) are known to induce insulin resistance, and a role for TLR4 has been implicated in this process. But FFAs are believed to be incapable of binding TLR4 directly. In a new study, Samir Bhattacharya and colleagues show that fetuin-A acts as an intermediary in this process by bindings FFAs and presenting them to TLR4. These results suggest fetuin-A as a new target to treat insulin resistance and diabetes.

Ultraviolet radiation induces an inflammatory response in the skin, but it remains unclear how cells in the skin detect this damage and trigger an inflammatory response. Richard L. Gallo and his colleagues report that ultraviolet radiation damages self noncoding RNA. These modified RNA are released from irradiated keratinocytes and act as a danger signal that is detected by Toll-like receptor 3 (TLR3), which is required for the induction of proinflammatory cytokine release and for radiation-induced immune suppression.

The mucosa of the large intestine mucosa is an effective vaccination site for induction of protective mucosal immunity against rectal or vaginal viral infection but clinically is impractical. Here Qing Zhu et al. have developed an oral delivery system that encapsulates vaccine into pH-dependent poly(DL-lactic-co-glycolic acid) (PLGA) nanoparticles coated with Eudragit to protect against the low pH and enzymatic destruction of the stomach. This approach was shown to selectively target the large intestine in mice and induce antigen-specific T and B cell responses similar to that observed with intracolorectal vaccination.

Joon-Mo Yang and colleagues have developed a new endoscopic technique for the in vivo imaging of internal organs, combining endoscopic ultrasound and photoacoustic endoscopy in a single instrument. In addition to improved resolution, imaging depth, multimodal contrast, and distal-end scanning, the new hybrid imaging modality can also provide functional information such as hemoglobin concentration and blood oxygenation. Feasibility is shown in vivo by simultaneous photoacoustic endoscopy and endoscopic ultrasound imaging of the upper and lower gastrointestinal tracts of rats and rabbits.