ES cell advantage in MS treatment
Researchers from Advanced Cell Technology and Imstem Biotechnology Inc. have generated mesenchymal stem cells from human embryonic stem cells (hESCs) and used them to treat mice with the animal version of multiple sclerosis. In direct comparison, cells from hESCs outperformed another type of mesenchymal stem cell that was derived from bone marrow, in part because the bone marrow-derived cells expressed the pro-inflammatory cytokine IL-6. Corresponding author Bob Lanza said that "our new method of generating mesenchymal stem cells (MSCs) from hESCs can be used to dramatically reduce the clinical symptoms (and prevent paralysis) of multiple sclerosis in the most widely accepted animal model of the disease. In stark contrast, adult bone marrow-derived MSCs (the most commonly used source of cells in clinical trials) only had a marginal effect on the disease." The work appeared in the June 5, 2014, issue of Cell Reports.
Make some noise to fight HIV
Researchers from the University of California at San Francisco have reported a new way to reactivate latent HIV, which could help cure people of the infection. HIV bedevils eradication efforts in part because of its reservoir – T cells that are infected with virus that is not replicating but could replicate. Current HIV drugs cannot touch such nonreplicating virus, but the mere presence of latently infected cells makes it impossible to stop taking the drugs. In their experiments, the team tested the idea of increasing the variability, or noise, of HIV gene transcription. Such increased variability can lead to increased efficiency in chemical reactions. They found that small molecules that increased variability synergized with HIV transcription activators, a class of drugs that has not been particularly successful as monotherapy. The authors concluded that "noise-modulating chemicals may provide novel probes for the physiological consequences of noise and an unexplored axis for drug discovery." They published their findings in the June 6, 2014, issue of Science.
BRCA2: Risk gene for – lung cancer?
Researchers from the National Institutes of Health and the British Institute for Cancer Research have shown that mutations in the BRCA2 gene, as well as the downstream checkpoint inhibitor gene CHEK2, raise the risk of lung cancer in smokers. BRCA2 mutations, which occur in about 2 percent of the population, strongly raise the risk for breast and ovarian cancers. In their work, the authors first combined the data from previous genomewide association studies on risk genes for lung cancer. They then imputed additional SNPs that were not looked at by the previous studies, by further combining the data with data from the 1,000 genomes project, and they found that smokers with BRCA2 mutations had a nearly doubled risk of the most common subtype of non-small-cell lung cancer. The work suggests that PARP inhibitors might be useful for treating some lung cancers and describes a novel method to impute SNPs. It appeared in the June 1, 2014, issue of Nature Genetics.
From membranes to insulin resistance
Scientists from the British University of Cambridge have identified patients with defects in phosphatidylcholine that had not only fatty liver, but also insulin resistance and diabetes. Phosphatidylcholine is a critical component of lipid membranes. In their work, the researchers identified two unrelated individuals who had lost both copies of the rate-limiting enzyme for phosphatidylcholine synthesis, PCYT1A. Both individuals had fatty liver and low HDL "good" cholesterol levels, but also severe insulin resistance and diabetes. The authors said that in addition to benefiting the individual patients, their findings added to the understanding of the biological functions of phosphatidylcholine. The study appeared in the June 2, 2014, issue of the Proceedings of the National Academy of Sciences.
Quadrapeutics: The fantastic four
Researchers from Rice University have combined four therapeutic modalities into a single cancer-fighting application they termed quadrapeutics. Their approach combined two separate types of nanoparticles, colloidal gold and encapsulate nanoparticles. Cancer cells transported those two drugs, which were targeted to the EGF receptor, into cells, where they were initially assembled but could be induced to explode by the application of a laser pulse. The assembled cluster also amplified the effects of X-rays. In their work, the authors were able to increase the effectiveness of chemoradiation on aggressive head and neck cancer by more than 15-fold in vivo. They concluded that their quadrapeutics method "combines four clinically validated components and transforms a standard macrotherapy into an intracellular on-demand theranostic microtreatment with radically amplified therapeutic efficacy and specificity." Their work appeared in the June 1, 2014, online issue of Nature Medicine.
Starring role for astrocytes
Researchers from Yale University have reported that astrocytes play an important role in the control of feeding. Astrocytes are the most abundant type of brain cells, but they have long been regarded as being mere supporters of neurons, which were assumed to do the heavy computational lifting. In their work, the authors showed that receptors for the hormone satiety hormone leptin, which plays important roles in appetite control, were expressed on astrocytes in the hypothalamus. Deleting those leptin receptors led to changes in the astrocyte circuitry with neurons that controlled feeding. Animals lacking the receptors showed less appetite suppression when they were treated with leptin, but ate more after a bout of fasting, than their wild-type cousins. "These data reveal an active role of glial cells in hypothalamic synaptic remodeling and control of feeding by leptin," the authors concluded. They published their findings in the June 1, 2014, online issue of Nature Neuroscience.
Psoriasis-inhibiting receptor found
Researchers from the British National Institute for Medical Research have identified a transcription factor that plays a role in psoriasis. Psoriasis and author autoimmune conditions clearly involve environmental factors, but how those environmental factors are sensed by the body is less clear than which genes are involved. The authors decided to look at one particular transcription factor, the aryl hydrocarbon receptor (Ahr), because it appears to play a role in maintaining the barrier function of the gut, suggesting it might play a similar role in skin. They found that Ahr signaling decreased inflammatory signaling in the skin in response to inflammation-inducing stimuli, and Ahr-deficient mice developed worse symptoms than their wild-type cousins when they were exposed to inflammatory stimuli. The authors concluded that "our data suggest a critical role for Ahr in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders." Their work appeared in the June 5, 2014, online edition of Immunity.
Preventing amyloid-beta earlier, in several ways
Researchers at New York University have identified a small molecule that inhibited the translation of amyloid precursor protein (APP), showing that such an approach could be one way to reduce the production of amyloid-beta, whose overproduction appears to be at the root of Alzheimer's disease. Attempts to reduce amyloid-beta levels by preventing APP processing have not been successful clinically. There are a number of reasons behind this failure, but one issue is that the APP-processing enzymes also process other proteins, leading to toxicity. The team decided to test whether intervening at an earlier step, namely the translation of APP mRNA into protein, could be a viable approach. They identified a small molecule, PAMP-2, that was able to cross the blood-brain barrier and specifically block APP translation, lowering the levels of the protein. Administering the compound chronically to transgenic Alzheimer's disease mice improved their memories. The authors concluded that their approach, if it pans out in the clinic, could be used preventively to forestall the amyloid-beta buildup that ultimately appears to cause neurotoxicity. Their work appeared in the June 3, 2014, online issue of the Annals of Neurology.
To sleep, perchance to learn – but why?
Scientists at New York University have identified one mechanism responsible for sleep's beneficial effects on memory consolidation. Sleep has long been known to benefit memory, but why this is the case is still largely mysterious. One controversy is centered on whether dendritic spines, which physically store memories, are eliminated or added during sleep. In their work, the authors found support for the latter case. They showed that when mice learned tasks, new dendritic spines formed, and sleeping prevented those spines from disappearing again. For the spines to be protected, it was necessary for neurons to be reactivated during sleep. Disrupting either sleep or the reactivation of the memory-storing neurons disrupted memory formation. These findings indicate that sleep has a key role in promoting learning-dependent synapse formation and maintenance on selected dendritic branches, which contribute to memory storage," the authors concluded. They published their results in the June 5, 2014, issue of Science.
'Positive' schizophrenia symptoms detangled
A team at St. Jude's Children's Research Hospital has developed a mouse model of the positive symptoms of schizophrenia, and used it to understand why those positive symptoms are sensitive to dopamine-targeting drugs. Schizophrenia symptoms can be classified as positive such as hallucinations, or negative such as social withdrawal and blunted emotions, and existing drugs work mainly on the positive symptoms. In their experiments, the authors tested mice with a genetic deletion found in schizophrenia, and showed that such animals had signaling defects in the pathway to the auditory cortex. The gene deletion leads to increased levels of dopamine receptors, due to lack of an inhibitor microRNA. The authors wrote their data "integrates several competing [schizophrenia] models," in particular, explaining both glutamate and dopamine signaling deficits and their relationship to positive symptoms. They published their results in the June 5, 2014, issue of Science.
By Anette Breindl, Science Editor