Study Outs Dendritic Cell Cross-Dressers
In response to a viral infection, antigen-presenting cells present antigens as, indeed, their name might suggest to the attentive reader to killer T cells. Researchers from the University of Washington have discovered a novel way in which antigen-presenting cells acquire those antigens in the first place: by getting them from other antigen-presenting cells. Previously, the only known ways for an antigen-presenting cell to get hold of an antigen was either by getting infected itself, or by engulfing another infected cell. But the authors showed that antigen-presenting cells can also pass antigens from one to the other through direct contact. From the point of view of the cross-dresser, this eliminates the need to process the antigens. The authors of an accompanying News and Views article suggested that though the cross-dressing road to antigen presentation is probably a less-traveled one, "cross-dressing may prove particularly important in cancer immunology, because the killing of infiltrating cross-presenting immune cells by T cells may be crucial for [tumor] eradication." Both paper and commentary were published in the March 31, 2011, issue of Nature.
Metabolomics Better Predictor than GWAS
Researchers from Massachusetts General Hospital have identified five amino acids whose levels can predict the development of diabetes, suggesting it may be able to identify at-risk individuals long before they develop any outright disease. The scientists repeatedly looked at the metabolic profiles of almost 2,500 individuals over a period of 12 years. About 200 of those individuals developed diabetes over the course of the study. Five amino acids had "highly significant associations" with the development of diabetes, and a combination of three of them isoleucine, phenylalanine and tyrosine could predict future disease. Individuals with high levels of the amino acids had an "at least fourfold" increased risk of developing diabetes in both the original study and a replication study in an independent group of people, making them a better predictor than any risk factors uncovered by genomewide association studies to date. The work was published in the March 20, 2011, online edition of Nature Medicine.
Misfolding Comes to Cancer
The tumor suppressor p53 is mutated in more than half of all human cancers. Scientists from the Belgian Katholieke Universiteit Leuven described last week how so-called structural mutations, which account for about a third of all p53 mutations, turn p53 from tumor suppressor into oncogene. In many cases, such structural mutants are prone to misfolding and aggregation. The process is somewhat similar to amyloid misfolding in neurodegenerative disease; but misfolded p53 also co-aggregates with other proteins, including p63 and p73, proteins with structural and functional similarities to p53. And as the authors pointed out, the consequences for cells are quite different. "In contrast to neurodegeneration, however, the cellular effects of p53 aggregation in cancer are associated with events that contribute to cell survival and proliferation rather than to cell death." The work appeared in the March 27, 2011, online edition of Nature Chemical Biology.
Lung Cancer Researchers Aim for AIMP2
Researchers at Korean Seoul National University have identified a new potential target for lung cancer therapies: the tumors suppressor AIMP2. It works by binding to tumor suppressor p53 and promoting cell death in response to DNA damage. In their work the authors showed that a version of AIMP2 lacking one of its exons also bound to p53, but was ineffective at promoting cellular suicide. The variant protein competed with regular AIMP2, preventing the regular version from binding and inducing suicide. When the authors used siRNA to suppress the variant AIMP2, tumor cell growth was slowed, suggesting, the authors wrote, that the variant form of the protein could be both "a therapeutic target and biomarker associated with lung cancer." The work was published in the March 31, 2011, issue of PLoS Genetics.
Researchers from the University of Alabama at Birmingham have found a way to keep gliomas from growing: by blocking the receptors they use to snake along blood vessels. Gliomas have a receptor for bradykinin, which is expressed on blood vessels; that receptor allows them to grow along blood vessels, ensuring a source of oxygen and nutrients and, incidentally, resulting in a diffuse growth pattern that is all but impossible to extract surgically. When the authors treated mice with the bradykinin receptor blocker icatibant (Firazyr, Shire) after transplanting human glioma cells into them, the proportion of cells that was able to find a blood vessel to grow along decreased from three-quarters to one-fifth of all cells. The authors concluded that targeting the receptors represents "an elegant and so far unexplored approach to treat gliomas." Their study was published in the March 30, 2011, edition of the Journal of Neuroscience.
Depression Chips Away at Telomeres
Researchers from the University of California, San Francisco, have found that the longer a person is exposed to depression, the shorter the telomeres of their white blood cells. Overall, depressed patients did not have shorter telomeres than controls, suggesting that shortened telomeres were not a risk factor for depression. But being above the media in terms of total lifetime spent depressed appeared to be worth about seven years' worth of aging as far as white blood cell telomere length was concerned. The findings held up when the team controlled for the age of their study subjects, showing that they were not simply a reflection of the fact that older subjects have had more time to be depressed. The authors concluded that "telomere shortening may progress with longer exposure to depression," but added that "prospective studies will be needed to explore this as well as the question of whether antidepressant treatment can attenuate this shortening." The work appeared in the March 22, 2011, issue of PLoS ONE.
How Early Is Too Early?
Researchers at the Mount Sinai School of Medicine have reported that the brains of mice that will eventually develop Alzheimer's disease use less glucose than control animals long before they have any cognitive impairment. The authors compared the mitochondria of mice overexpressing beta amyloid to those of normal animals, and found that as soluble beta amyloid rose, the mitochondria were impaired in their capacity to use glucose and generate energy. They claimed that their method can show impairments at a time that would be equivalent to 20 years before disease onset in humans. The findings open the door for early intervention, but may also bring the problems of Alzheimer's diagnosis from one extreme currently, it can be diagnosed with certainty only after death to the other, which is more typical for genetic risk factors at this point: a potentially crushing diagnosis that comes decades before the disease. The study was published in the March 2011 issue of Translational Neuroscience.
Why Cancer Cells Squat in Bone
Metastases do not pop up randomly. The metastases of different primary tumors will preferentially set up shop in different organs. Prostate and breast cancer cells will show up in the bone at a higher rate than in other cancers. Researchers from the University of Michigan have found a molecular explanation for why. Circulating prostate cancer cells are attracted to the bone marrow's stem cell niche, which is the home of the body's blood-forming stem cells. After taking up residence, the tumor cells compete with blood-forming stem cells. Because part of the role of the stem cell niche is to keep cells from dividing most of the time, the work may explain why chemotherapy, which targets proliferating cells, is often ineffective in eradicating cells that are in the stem cell niche. The work was published in the March 23, 2011, of the Journal of Clinical Investigation.
Making Leukemia Cells Play Nice
A team from the University of California, San Francisco, reported that in preclinical studies, treatment with a kinase inhibitor was effective against the symptoms of juvenile myelomonocytic leukemia (JMML), though it did not kill the leukemic cells. That type of leukemia is due to a mutation in the oncogene KRAS. The scientists used an inhibitor of another kinase, MEK, to treat mice with KRAS mutations. Mice that were treated with the MEK inhibitor still had high levels of RAS-mutated cells in their bone marrow after treatment. But they produced more red blood cells and fewer white blood cells than untreated mice, and the anemia commonly associated with JMML also disappeared. The authors suggested that this is due to a "rebalancing" of blood cell lineage development from blood stem cells, and noted that although their treatment does not cure JMML, the results of their work suggested that it may nevertheless be able to cause clinical remissions, at least for a time. Study results were published in the March 30, 2011, online edition of the journal Science Translational Medicine.
Microbes Have SNPs, Too
Clinicians have long known that a bacterial infection can result in life-threatening disease, or no disease at all. Partly, that is due to bacterial locations Staph aureus, harmless on the skin, can be fatal in the bloodstream. But small differences between bacterial strains can also lead to big differences in their effects. Scientists from the Methodist Hospital Research Institute, of Houston, have described single-nucleotide differences that strongly affect the virulence of Group A streptococcal bacteria. The authors showed that changes to a single nucleotide in other words, a SNP could affect the virulence of a strain, particularly if it was located within a regulatory protein by the name of ropB. The authors said their data showed how "an unbiased, whole-genome sequence analysis of populations of clinical bacterial isolates creates new avenues of productive investigation into the pathogenesis of common human infections." Their work was published in the March 30, 2011, issue of the Journal of Clinical Investigation.
Anette Breindl, Science Editor