Discovering Multiple Forms of Multiple Sclerosis

By analyzing the RNA transcripts in blood cells of subjects with multiple sclerosis, a team at Brigham and Women's Hospital has been able to identify two subtypes of the disease early in its course. Multiple sclerosis patients differ greatly in how active their disease is. But currently, doctors have no way to predict at diagnosis who is likely to have a more active disease, and so benefit from more aggressive treatment. In their study, the authors analyzed the RNA transcripts of blood cells in freshly diagnosed patients, before treatment had started, and found that the transcriptional profiles fell into two separate groups. One group had a higher expression of genes related to lymphocyte signaling. In replication experiments, such patients were more likely to experience a flare-up of their disease during initial treatment with either of the two standard options for multiple sclerosis. The work appeared in the Sept. 27, 3012, issue of Science Translational Medicine.

Breast Cancer Subdivided into Four Types

The Cancer Genome Atlas Network turned its analytical powers to breast cancers, and reported results from the detailed analysis of several hundred breast tumors with six different methods including whole genome and exome sequencing, copy number analysis, epigenetic XX and protein expression studies. Using those methods, the team developed a classification system for breast cancer that recognizes four main subtypes, rather than the three-type classification used currently. They also found that one of those subtypes, basal-like breast cancer, was molecularly quite similar to ovarian cancer, suggesting that the two might be sensitive to similar drugs. The study was published in the Sept 23, 2012, advance online edition of Nature.

Current Ideas on Macrophages Upside Down

Foamy macrophages are thought to set off inflammation, and atherosclerosis, when they get stuck in cell walls while responding to excessive cholesterol. But researchers from the University of California at San Diego have presented evidence that macrophages themselves actually set off anti-inflammatory gene expression in the cell walls, through the effects of the cholesterol precursor desmosterol. When plenty of desmosterol is present, cells stop producing cholesterol and instead activate pathways to break it down. Atherosclerosis resulted when desmosterol somehow became ineffective at inducing cholesterol breakdown. The authors suggested that developing synthetic analogues of desmosterol might be a new way to treat cardiovascular disease. Their findings were published in the Sept. 28, 2012, issue of Cell.

One Cancer Drug Improves Progeria . . .

A team from Brown University and Harvard University reported results from a clinical trial using the experimental cancer drug lonafarnib to treat children who suffer from the extreme premature aging known as Hutchinson-Gilford progeria syndrome. Given the extreme rarity of the disease, the trial size of 25 children corresponded to three-fourths of the global population with progeria that had been identified when the trial began, though the identified population has since nearly doubled. They were treated with lonafarnib for at least two years, and the investigators measured weight gain, skeletal stiffness and blood vessel stiffness, over the course of treatment. About a third of the children improved rate of weight gain, while skeletal stiffness increased and blood vessel stiffness decreased with treatment. Low-frequency hearing also improved. Seven other measurements, including echocardiogram readings and insulin resistance, were unaffected. But the authors noted that each treated child improved on at least one of the primary outcome measures. The results appeared in the Sept. 24, 2012, advance online edition of the Proceedings of the National Academy of Sciences.

. . . Another, Memory Loss

The formation of amyloid beta oligomers leads to memory loss in the development of Alzheimer's disease. Those oligomers, however, have many interaction partners within cells, leaving scientists unclear as to how they ultimately interfere with learning. By screening for compounds that could reverse memory loss in transgenic fruit fly and mouse models of the disease, scientists at the Cold Spring Harbor Laboratories have identified two clinically available drugs and three additional compounds that improved memory in such animal models. Unexpectedly, those compounds appeared to act via the same mechanism – they prevented amyloid beta from activating the epidermal growth factor receptor, which is mutated in a subset of lung cancers and target of Tarceva (erlotinib, Roche AG and Astellas Pharma Inc.) and Iressa (gefitinib, AstraZeneca plc). The authors concluded that "EGFR is a preferred target for treating Abeta-induced memory loss." They published their findings in the Sept. 24, 2012, advance online edition of the Proceedings of the National Academy of Sciences.

Sometimes, the Problem Is in What's Unwritten

Researchers from Columbia University used transcriptome analysis to identify a form of alpha-synuclein with a longer untranslated region that appeared to be a starting point for the pathological changes in Parkinson's disease. In Parkinson's, alpha-synuclein clumps and forms so-called Lewy bodies, which are toxic to neurons that use dopamine as a neurotransmitter. But why alpha-synuclein clumps in Parkinson's and how that preferentially kills some neurons is unclear. The authors used a form of gene expression analysis, differential co-expression analysis, that attempts to differentiate transcripts whose expression levels changes lead to disease from those whose levels are changed as a result of disease. They identified the longer alpha-synuclein as a transcript that is likely to initiate pathological changes in Parkinson's disease. Longer untranslated regions can lead proteins to be localized and processed near mitochondria, and so the findings offered an explanation for why alpha-synuclein moves away from synapses and toward mitochondria in Parkinson's. The paper appeared in the Sept 26, 2012, issue of Nature Communications.

GWAS Goes Meta

Scientists from the Chinese Beijung Genomics Institute-Shenzhen have identified components of the gut microbiome that vary between individuals with Type II diabetes and nondiabetic controls. Genomewide association studies to date have focused on the genomes of individuals. But recent studies have made it increasingly clear that the gut microbiome – sometimes called the metagenome – plays key roles in an individuals' metabolism. The authors sequenced the gut microbiomes of about 350 individuals, roughly half of whom had Type II diabetes, and identified a signature of 50 SNPs that differed between the two groups. The signature might be useful as a diagnostic tool. The authors also plan to test, through gut microbiome transplantation experiments, whether the diabetes-associated microbiome composition is a cause of diabetes or its consequence. The work appeared in the Sept. 27, 2012, issue of Nature.

VEGF-B Blockade Fights Diabetes

Researchers from the Swedish Karolinska Institutet have discovered a potential new way to fight diabetes: through blocking the signaling of vascular endothelial growth factor B or VEGF-B. An important feature of diabetes is that excess fats are deposited into muscle cells, which then become resistant to insulin. The authors found that knocking out VEGF-B in genetically diabetic mice prevented excessive fat uptake into muscles and prevented insulin resistance. Antibodies that blocked VEGF signaling improved glucose tolerance and pancreatic islet cell function, and had positive effects on several other symptoms of diabetes and metabolic syndrome. Diabetic symptoms were also improved in mice who had diabetes due to eating a high-fat diet, rather than due to their genetic makeup. The authors argued their results showed that "the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and Type II diabetes, and that this barrier can be maintained by inhibition of VEGF-B signaling. We propose VEGF-B antagonism as a novel pharmacological approach for Type II diabetes." The paper was published in the Sept. 27, 2012, issue of Nature.

Fragile X Affects Endocannabinoids

A team from the University of California at Irvine, the French INSERM Institute and the Hungarian Academy of Sciences' Institute of Experimental Medicine added another transmitter to those affected in Fragile X syndrome. The loss of the Fragile X Mental Retardation Protein (FMRP) affects synaptic plasticity in the hippocampus and cerebellum, and those effects likely underlie the cognitive effects that are seen in Fragile X syndrome. But anxiety and social withdrawal are also symptoms of the disorder. In their work, the team showed that FMRP knockout mice also had changes to their neural plasticity in another brain area, the ventral striatum, and that those changes were mediated by endocannabinoids, or marijuana-like transmitters produced by the brain. The paper appeared in the Sept 26, 2012, issue of Nature Communications.

LIFR Predicts Breast Cancer Metastasis, or Lack

It's called the leukemia inhibiting factor receptor (LIFR). But researchers from MD Anderson Cancer Center have found that apparently, it inhibits breast cancer metastasis, too. The authors were searching for targets of the metastasis-promoting microRNA miR-9, and identified 56 genes that had a binding site for miR-9. Of those 56 genes, only LIFR appeared to be regularly down-regulated in clinical breast cancer samples, and so the authors performed both loss- and gain-of-function experiments with the protein. They found that in metastatic cell lines that had lost LIFR expression, restoring that expression prevented metastasis when the cells were xenotransplanted. But in clinical breast cancer samples, lower expression of LIFR correlated with life expectancy. The authors said their findings identify LIFR as a protein that can be used in breast cancer prognosis. They also noted that "elevating the expression of metastasis suppressor proteins" – of which more than 20 have been identified – "has been useful preclinically and in clinical trials. . . . We envision that therapeutic intervention centered on restoring LIFR expression or function could be useful for blocking breast cancer metastasis." Their work appeared in the Sept. 23, 2012, advance online edition of Nature Medicine.

– Anette Breindl, Science Editor