Longevity Data: Retracted, Reanalyzed, Republished

Scientists from Boston University have reanalyzed and republished data on genetic signatures of exceptional longevity that were first published in 2010, and then retracted over methodological concerns. In the original work, the authors identified a gene signature of about 150 SNPs that predicted a long life span and health span for those individuals who possessed it. Notably, disease risk variants such as the Alzheimer's ApoE4 variant were as frequent in the long-lived individuals as in controls. The reanalysis comes to the same basic conclusion, but removed several of the SNPs that were part of the original signature. In a comment published with the reanalysis, the editors at PLoS noted that "while we recognize that aspects of this study will attract attention owing to the history and the strong claims made in the paper, the handling editor, Greg Gibson, made the decision that publication is warranted" overall, adding that "we trust that publication will facilitate full evaluation of the study." The reanalysis was published online in PLoS ONE on Jan. 18, 2012.

Why Statins Treat Some Cancers, Too

Researchers from Columbia University have worked out why cholesterol-lowering statins appear to keep breast tumors at bay in some patients. Using three-dimensional cell cultures, the authors found that mutant p53 led cells to become unable to form so-called acinar structures, which keep breast cells organized – among other things, they help to prevent out-of-control cell division – under normal circumstances. In their work, the authors found that when p53 was mutated, the activity of the cholesterol-building mevalonate pathway was sharply increased. Treating p53-mutant tumor cells with statins prevented that activation, and in the cell culture, treated cells tended to go back to forming three-dimensional structures. The authors concluded that their findings "implicate the [cholesterol-synthesizing] mevalonate pathway as a therapeutic target for tumors bearing mutations in p53." Their work appeared in the Jan. 20, 2012, issue of Cell.

After Stem Cells from Fat, Fat from Stem Cells

You'd think that if there's any one cell type that there is too much of, it's fat cells. But while that may be true for most individuals, the laboratory is another matter: Though fat cells are easily harvested, they are hard to maintain in culture. But now, researchers from Harvard University have managed to make both brown and white fat cells from induced pluripotent stem cells. In cell culture, the cells kept dividing for several weeks, and "when transplanted into mice, the programmed cells gave rise to ectopic fat pads with the morphological and functional characteristics of white or brown adipose tissue," the authors wrote, adding that "these results indicate that the cells could be used to faithfully model human disease." The scientists reported their method for making fat cells in the Jan. 15, 2012, advance online edition of Nature Cell Biology.

Barriers Keep Grip via Extra Chromosome Sets

During organ growth, some types of tissue are faced with a unique challenge. Tissues that form barriers – such as the blood-brain barrier, and also the skin – need to grow with the organs they protect, and the most obvious way to do so would be via cell division. But such cell division would break open the protective seal between cells – technically, the tight junctions – that are barrier cells' raison d'etre. Now, scientists from the Massachusetts Institute of Technology' s Whitehead Institute have demonstrated that blood-brain barrier cells in the fruit fly solve that conundrum by growing via polyploidy – that is, they double their chromosomes but do not divide. Such cells can grow without damage to their junctions. The authors concluded that the appearance of cells with multiple chromosome copies "likely is a conserved strategy to coordinate tissue growth during organogenesis, with potential vertebrate examples." Their work appeared in the Jan. 1, 2012, online issue of Genes & Development.

After Radiation, a Trip to Everest?

Whole-brain radiation is a frequent treatment for brain tumors, since many of them cannot be surgically removed. But it leads to cognitive impairments in up to half of the patients who need to be treated with the method. Now, scientists at the University of Oklahoma Health Sciences Center have described a way to reverse such impairments: hypoxia, though that is not normally associated with improving memory. The authors first treated mice with whole-brain irradiation, and one month later, housed them under conditions of either low or normal oxygen for four weeks. Radiation treatment led to learning impairments in the mice, but four weeks under low oxygen completely reversed those deficits. The authors concluded that "processes of learning and memory, once thought to be permanently impaired after [whole-brain radiation therapy], can be restored." Their studies appeared in the Jan. 18, 2012, online edition of PLoS ONE.

Emphysema: An Autoimmune Disease?

Researchers from the Baylor College of Medicine gained new insight into the immune system's contributions to emphysema. The authors showed that antigen-presenting cells from the lungs of smokers can induce several types of T cells. In their studies, the authors found cigarette smoke induced the expression of the cytokines interferon-gamma and interleukin-17A in several types of T cells, and those cytokines exacerbated the symptoms of emphysema. When antigen-presenting cells of mice with emphysema were transplanted into healthy mice, those mice could develop emphysema even without being exposed to cigarette smoke. The long-term effects of the antigen-presenting cells may explain why emphysema can continue to grow worse even if smokers quit. The gene for the glycoprotein osteopontin was highly expressed in the emphysema-causing antigen-presenting cells, and the authors showed that expression was necessary for their harmful effects. They noted the osteopontin-signaling pathway of antigen-presenting cells could potentially be targeted for the development of new therapeutics for emphysema, which, "exacts a large and rapidly increasing toll on human health and society" along with other smoking-related illnesses. Their work appeared in the Jan. 18, 2012, issue of Science Translational Medicine.

Anti-Angiogenesis Approach Can Backfire

Researchers from Harvard University reported that attempting to control angiogenesis via targeting pericytes, though that approach did indeed retard tumor growth, is unlikely to be a promising anticancer strategy: It also increased metastases. Pericytes are a type of cell that lines blood vessels, and the team created mice whose pericytes could be killed by drug treatment. When they killed pericytes in mice with breast tumors, the tumors shrank by 30 percent. But in the same time period, animals lacking pericytes had three times as many metastases in their lungs. Treatment with Gleevec (imatinib, Novartis AG) and Sutent (sunitinib, Pfizer Inc.), which are not anti-angiogenic drugs but do target pericytes, had the same effects in mice. Finally, the team showed that human breast tumor samples with low numbers of pericytes in tumor vasculature correlated with higher chances of metastasis and low survival rates. The findings were published in the Jan. 17, 2012, issue of Cancer Cell.

. . . For Lots of Reasons

In the same Jan. 17, 2012, issue of Cancer Cell, scientists from the Dutch VU University Medical Center in Amsterdam, the Netherlands, reported on yet another pitfall of anti-angiogenesis treatments: They can decrease the effectiveness of chemotherapy drugs. In their studies, the authors used imaging to test the effects that treatment with Avastin (bevacizumab, Roche AG) had on subsequent chemotherapy uptake in lung cancer patients. They found that Avastin treatment reduced the influx rate of chemotherapy, and that effect persisted for several days. They concluded that "the clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs."

When Energy Conservation Is Bad

Researchers from the University of Pennsylvania have discovered that blocking a particular kinase – AMP-activated protein kinase, or AMPK – may protect motor neurons from the damage they suffer in amyotrophic lateral sclerosis (ALS). The authors tested the effects of AMPK knockdown because the enzyme that is mutated in ALS, superoxide dismutase, can activate AMPK by disrupting energy production in the mitochondria. The cell responds by conserving energy, but the way it does so – among other things, by decreasing protein synthesis – might damage motor neurons. The team did indeed find that neurons expressing mutant SOD were far less likely to die if their AMPK was either knocked down or inhibited pharmacologically. The authors said their data supported the view that metabolic abnormalities contribute to the symptoms of ALS. Their work was published in the Jan. 18, 2012, issue of the Journal of Neuroscience.

No Male Liver Cancer Patients in Foxholes, Either

Scientists from the University of Pennsylvania have worked out why men are so much more likely than women to get liver cancer. Females appear to be protected by estrogen, since estrogen treatment lowers the liver cancer rate in male mice, and ovariectomy raises it in females. But how estrogen protects against liver cancer has been unclear. In their work, the authors showed that mice lacking the transcription factors Fox1a and Fox2a had the opposite risk ratio of normal animals, with females much more likely to develop liver cancer after treatment with a carcinogen. Gene expression of a number of genes appears to be jointly regulated by Fox1a or Fox2a and estrogen or androgen receptors, and when the transcription factors are lacking, gene expression patterns are changed in a way that affects liver cancer risk. The authors also looked at FOX1a and FOX2a binding sites in liver cancer samples from women, and found a number of SNPs in them. They believe that looking for such SNPs may be one way to predict the risk of liver cancer in women. The experiments were published in the Jan. 19, 2012, issue of Cell.

– By Anette Breindl, Science Editor