Volume 16 Issue 10, October 2010

On 26 October 1910, the Rockefeller Institute for Medical Research in New York (now Rockefeller University) admitted the country's first research participant in a hospital dedicated completely to clinical studies. Emeritus professor Jules Hirsch, a metabolism researcher who joined Rockefeller in 1954, spoke with Roxanne Palmer about the clinical center's impact on biomedical research and education.

A hundred years after scientists first linked histamine molecules to allergies, the study of histamine pathways is in the midst of a revival, thanks in part to the discovery of a new type of receptor. This fourth known histamine receptor now provides an attractive drug target for seasonal allergies, asthma and possibly even cancer. Erica Westly traces the histamine reaction.

Over the past eight years, the state of Florida has invested close to a billion dollars to attract renowned research organizations to open up shop within its borders. But even with the arrival of several heavyweights, including the Scripps Research Institute and the Max Planck Institute, some continue to question whether the investment was worthwhile. Christopher Mims reports.

Patient advocates are often dismissed by the scientific establishment for focusing too much on cures and treatments at the expense of basic research. But advocates help create a biomedical research enterprise that is more attuned to the needs and preferences of the public—the very people who ultimately support and are meant to benefit from the enterprise. As such, scientists and government officials would be wise to heed patient advocates' advice.

Mobilization of hematopoietic stem cells (HSCs) from the bone marrow is the standard method to collect grafts for stem cell transplants, but sometimes insufficient HSCs are mobilized. A new study suggests that epidermal growth factor receptor (EGFR) inhibition can augment mobilization, bringing us one step closer to an universal method to obtain HSCs for transplantation (pages 1141–1146).

Just as a Bob Marley tune can elicit a visceral pull, a rhythmic awakening can shake up metabolism, with a new study in mice showing that cryptochrome (CRY) in the liver controls glucose levels during fasting and improves insulin sensitivity—introducing a new possible therapy for type II diabetes (pages 1152–1156).

Uncovering how the immune system of the mucosa surmounts allergic reactions may open new avenues to treat inflammatory conditions in the gut. New findings in mice now show that a C-type lectin receptor in dendritic cells (DCs) protects against food antigens that cause systemic anaphylaxis—promoting oral tolerance (pages 1128–1133).

Bacterial pneumonia can be a life-threatening disease that causes lung injury. A new study shows that accumulation of a phospholipid in the lung fluid in mice and humans worsens gas exchange during the microbial infection (pages 1120–1127). Clearance of this lipid may improve lung function during infection.

The tumor suppressor p53 is inactivated by genetic mutations in many cancers, except for neuroblastoma. New findings show that this cancer reversibly inhibits p53 through a microRNA, miR-380-5p (pages 1134–1140). Blocking it to restore p53 function may be an attractive therapeutic option for neuroblastomas.

Much of how the human host responds to a tumor and to anticancer therapy is still not fully fleshed out. The cytokines and other mediators involved in this response may be both allies and enemies in the quest for more effective treatments or even a cancer cure. In 'Bedside to Bench', Robert Kerbel and John Ebos discuss recent human studies in healthy individuals and people with minimal residue or no disease showing release of host-derived cytokines after antiangiogenic therapy. The increase in proangiogenic factors such as VEGF and PIGF and other cytokines involved in metastasis and tumor repopulation in a host may threaten therapeutic success but may also suggest new prognostic markers and other treatment strategies. In 'Bench to Bedside', Michael Karin and Florian Greten peruse how using JAK2 inhibitors to block STAT3 in tumors could halt cancer progression. JAK2 inhibitors, already being tested in clinical trials to treat myeloproliferative diseases, may also prove valid as anticancer drugs.

Passive transfer of high doses of neutralizing antibodies can protect nonhuman primates against infection with simian HIV (SHIV). Ng et al. now report that low levels of neutralizing polyclonal antibodies plus a neutralizing monoclonal antibody do not prevent infection with SHIV, but do delay peak viremia, modulate CD4⁺ T cell decline and promote the de novo generation of neutralizing antibodies in macaques.

Mutations in ATP8b1 are found in certain individuals susceptible to pneumonia. Ray et al. now report that bacterial pneumonia is associated with elevated levels of the phospholipid cardiolipin in airway fluids, that ATP8b1 is a cardiolipin importer and that excessive cardiolipin in the lung contributes to impaired lung function. The findings suggest that ATP8b1 might be a new therapeutic target for the treatment of pneumonia.

A C-type lectin receptor, SIGNR-1, helps dendritic cells in the gut induce oral tolerance. Sugar-modified antigens might therefore be used to induce oral tolerance to food-induced anaphylaxis.

The characterization of miR-380-5p–driven p53 repression provides a new mechanism for downmodulation of stress-induced antiproliferative responses in wild-type p53 contexts, including embryonic stem cells and neuroblastoma tumors. miR-380-5p potentiates Ras-induced mammary gland tumorigenesis and is frequently elevated in human neuroblastomas. miR-380-5p inactivation induces tumor cell death and shows therapeutic efficacy in orthotopic neuroblastoma models.

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 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.

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.

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.

From a therapeutic standpoint, one of the main drawbacks of artificial electrical stimulation of muscle is that large, fatigable motor units are recruited before smaller units, which is opposite to the normal physiological recruitment pattern. Researchers from Stanford University have circumvented this problem by stimulating muscle optically rather than electrically, providing enhanced functional performance and potential applications for the technique in neuromuscular physiology, neuroprosthetics and neurorehabilitation.