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Archive - 2014

December 7th

Micro RNAs in Circulating Exosomes May Provide Prognostic Tool for Multiple Myeloma

The "molecular mail" sent by multiple myeloma cells provides clues as to how well patients with the disease are likely to respond to treatment, according to a study being presented at the annual meeting of the American Society of Hematology (ASH) by researchers at the Dana-Farber Cancer Institute. The findings, presented in poster form on December 6, 2014, may ultimately guide doctors in deciding which therapies are best for individual patients with multiple myeloma, the study authors say. The study focused on exosomes (see image), tiny sacs that cells release into the bloodstream as a way of communicating with other cells. The exosomes contain microRNA molecules, fragments of RNA that help control the activity of genes. The type of microRNA molecule in each exosome holds a specific message - an order to be conveyed to another cell. In the study, researchers isolated exosomes from the blood of 10 patients with multiple myeloma and five healthy volunteers, and extracted the microRNA molecules. They found the two groups harbored sharp differences in the levels of many microRNAs. The researchers then tested for 24 specific types of microRNAs in blood samples from 112 multiple myeloma patients who were participating in a French clinical trial of a new drug. By tracking the results against several years of patients' health data, they explored whether high or low levels of any of these microRNAs were associated with a particularly good or bad prognosis. They found that patients with low amounts of two microRNAs - known as let-7e and 106b/25 - survived for less time before their disease began to worsen than did the other patients.

December 6th

Unprecedented Benefit Seen in Three-Drug Treatment for Multiple Meloma

In the treatment of multiple myeloma, the addition of carfilzomib to a currently accepted two-drug combination produced significantly better results than using the two drugs alone, according to a worldwide research team led by investigators from the Mayo Clinic. The findings were reported online on December 6, 2014 in an open-access article in the New England Journal of Medicine, and will be presented on December 7, 2014 at the annual meeting of the American Society of Hematology (ASH), held in San Francisco. Interim analysis of the ASPIRE clinical trial, which enrolled 792 patients with relapsed multiple myeloma from 20 countries, found an "unprecedented" prolongation of the time patients were free of disease progression, says the study's lead investigator, Keith Stewart, M.B., Ch.B, a Mayo Clinic oncologist and Professor of Medicine in Arizona. "Patients taking three drugs -- carfilzomib, lenalidomide, and dexamethasone -- stayed free of disease progression for 26 months on average," he says. "No one has reported anything like this before for relapsed multiple myeloma." Researchers found that adding carfilzomib to standard treatment (lenalidomide and dexamethasone) resulted in 8.7 months of longer remission, almost 50 percent longer than the standard two-drug combination (26.3 months versus 17.6 months). The number of patients who responded to treatment was also significantly improved by adding carfilzomib to standard treatment -- 87.4 percent versus 66.9 percent-- and more than three times more patients had no detectable disease after the three-drug treatment (31.8 percent versus 9.3 percent). Although results were preliminary, there was also a trend toward improved overall survival, Dr. Stewart says. "Importantly, patients on the three-drug cocktail also reported a better quality of life despite a higher intensity of treatment," he says.

Smoking Associated with Mosaic Loss of Y-Chromosome

In a new study, published online on December 4, 2014 in Science, researchers at Uppsala University, and collaborators, demonstrate an association between smoking and loss of the Y-chromosome (image) in blood cells. The researchers have previously shown that loss of the Y-chromosome is linked to cancer. Because only men have the Y-chromosome, these results might explain why smoking is a greater risk factor for cancer among men and, in the broader perspective, also help explain why men in general have shorter lifespans. Smoking is a risk factor for various diseases, not only lung cancer. Epidemiological data show that male smokers have a greater risk of developing cancer outside the respiratory tract than female smokers. In the present study, which is the result of an international collaboration, the researchers discovered an association between smoking and genetic damage among men that might explain this sex difference. “We have previously in 2014 demonstrated an association between loss of the Y-chromosome in blood and greater risk for cancer. We now tested if there were any lifestyle- or clinical factors that could be linked to loss of the Y-chromosome. Out of a large number of factors that were studied, such as age, blood pressure, diabetes, alcohol intake, and smoking, we found that loss of the Y-chromosome in a fraction of the blood cells was more common in smokers than in non-smokers,” says Lars Forsberg, Ph.D., researcher in the Department of Immunology, Genetics, and Pathology, Uppsala University, and the key scientist responsible for the study. The association between smoking and loss of the Y chromosome was dose-dependent, i.e. loss of the Y-chromosome was more common in heavy smokers compared to moderate smokers.

December 5th

Huge Potential of Exosomes Is Major Focus of Society's Annual Meeting October 2014

Over two hundred visionary scientists, pragmatic physicians, and savvy biotech sales reps from the United States and around the world gathered in California from October 10-13, 2014 to discuss the latest advances in research and technology related to exosomes, a new and extremely hot area of science with possibly huge potential for game-changing applications in clinical medicine. The occasion was the fourth annual meeting of the American Society for Exosomes and Microvesicles (ASEMV). The site was the magnificently beautiful Asilomar Conference Grounds bordering the Pacific Ocean on Northern California’s Monterey Peninsula approximately 100 miles south of San Francisco. This meeting was organized by Stephen Gould, M.D., President of the ASEMV, Professor of Biological Chemistry at The Johns Hopkins University School of Medicine, and an expert on exosome biogenesis; and by Douglas Taylor, Ph.D., Secretary-General of the ASEMV, formerly a professor at the University of Louisville, an exosome pioneer, and now the chief scientific officer (CSO) of a year-old start-up company called Exosome Sciences, Inc., located just outside Princeton, New Jersey, and a majority-owned subsidiary of Aethlon Medical, Inc. There was also notable organizational assistance from Sasha Vlassov, Ph.D., from Life Technologies (Thermo Fisher Scientific, Inc.), from Travis Antes, Ph.D., of System Biosciences, Inc. (SBI), and from many of the graduate students in Dr. Gould’s lab.

December 4th

Centipede Genome Sequenced; Gives Insight into Evolution; No Vision or Circadian Clock Genes Found

An international collaboration of scientists including Baylor College of Medicine has completed the first genome sequence of a myriapod, Strigamia maritima - a member of a group of venomous centipedes that care for their eggs - and uncovered new clues about their biological evolution and unique absence of vision and circadian rhythm. Over 100 researchers from 12 countries completed the project. They published their work online on November 25, 2014 in the open-access journal PLOS Biology. “This is the first myriapod and the last of the four classes of arthropods to have its genome sequenced,” said Dr. Stephen Richards, Assistant Professor in the Human Genome Sequencing Center at Baylor, where the sequencing of the project was completed, and the corresponding author on the report. “Arthropods are particularly interesting for scientific study because they diverged into more species than any other animal group as they adapted in many ways to conquer the planet. The genome of the myriapod in comparison with previously completed genomes of the other arthropod classes gives us an important view of the evolutionary changes of these exciting species.” Dr. Ariel Chipman, of the Hebrew University of Jerusalem in Israel, Dr. David Ferrier, of The University of St. Andrews in the United Kingdom, and Dr. Michael Akam of the University of Cambridge in the UK, together with Dr. Richards served as key players in the collaboration. “The arthropods have been around for over 500 million years and the relationship between the different groups and early evolution of the species is not really well understood,” said Dr. Chipman, Associate Professor at the Hebrew University.

Cost-Effective, Exosome-Based Blood Test Will Detect Specific miRNA Profile Predictive of Early-Onset Alzheimer’s Disease

A non-invasive blood test that could be used to diagnose early-onset Alzheimer’s disease (AD) with increased accuracy has been developed by University of Melbourne researchers. The research team previously determined that changes in the brain occur two decades before patients show signs of dementia. These changes can be detected through expensive brain imaging procedures. The new early-detection blood-test, which is based on profiling miRNAs carried in serum-borne exosomes, could predict these particular changes and a person’s risk of developing AD much earlier than is currently possible. The blood test has the potential to improve prediction for AD to 91 per cent accuracy. However, this needs to be further tested in a larger population across three to five years, due to AD being a progressive disease. In an initial trial group using the blood test, one in five healthy participants with no memory complaints tested positive. On further medical investigation using brain-imaging techniques, these patients showed signs of degeneration in the brain resembling AD features. Lead researcher Professor Andrew Hill (photo), from the Department of Biochemistry and Molecular Biology and the Bio21 Institute at the University of Melbourne, said the blood test would significantly advance efforts to find new treatments for the degenerative disease and could lead to better preventative measures prior to diagnoses. “This blood test would be crucial to the development of therapeutic and preventative drugs for AD. It can be used to identify patients for clinical drugs and monitoring improvement on treatment,” he said. The high accuracy of this blood test for the brain disorder comes from the ability to harvest protected bubbles (exosomes) of genetic material, called microRNA, found circulating in the bloodstream.

November 28th

Bitter Food, but Posssibly Sweet Medicine, from Cucumber Genetics

High-tech genomics and traditional Chinese medicine come together as researchers identify the genes responsible for the intense bitter taste of wild cucumbers. Taming this bitterness made cucumber, pumpkin, and their relatives into popular foods, but the same compounds also have potential to treat cancer and diabetes. "You don't eat wild cucumber, unless you want to use it as a purgative," said Dr. William Lucas, professor of plant biology at the University of California, Davis, and coauthor on the article published in the November 28, 2014 issue of Science. That bitter flavor in wild cucurbits -- the family that includes cucumber, pumpkin, melon, watermelon, and squash -- is due to compounds called cucurbitacins. The bitter taste protects wild plants against predators. The fruit and leaves of wild cucurbits have been used in Indian and Chinese medicine for thousands of years, as emetics and purgatives, and to treat liver disease. More recently, researchers have shown that cucurbitacins can kill or suppress growth of cancer cells. Bitterness is known to be controlled by two genetic traits, "Bi" which confers bitterness on the whole plant and "Bt", which leads to bitter fruit. In the new work, Dr. Lucas, Dr. Sanwen Huang at the Chinese Academy of Agricultural Sciences, and colleagues employed the latest in DNA sequencing technology to identify the exact changes in DNA associated with bitterness. They also tasted a great many cucumbers. "Luckily this is an easy trait to test for," Dr. Lucas said.

November 27th

Pseudouridylation Found to Occur Naturally in mRNA

The so-called central dogma of molecular biology—that DNA makes RNA which makes protein—has long provided a simplified explanation for how genetic information is deciphered and translated in living organisms. In reality, of course, the process is vastly more complicated than the schema first articulated nearly 60 years ago by Nobel Laureate Francis Crick, co-discoverer of the DNA’s double-helix structure. For one, there are multiple types of RNA, three of which—messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA)—are essential for proper protein production. Moreover, RNAs that are synthesized during the process known as transcription often undergo subsequent changes, which are referred to as “post-transcriptional modifications.” Multiple such RNA modifications have been documented over the years, although the precise functions and significance of many of these have been shrouded in mystery. Among the most common post-transcriptional modifications is pseudouridylation, during which the base nucleoside uridine—the ‘U’ of the four base RNA nucleosides abbreviated as A, C, G, and U—has its chemical structure altered to form a molecule known as pseudouridine (ψ) (see image). To date, ψ has been found in abundance in tRNA, rRNA, and small nuclear or snRNA, but was thought not to exist in mRNA. Deploying sophisticated high-throughput sequencing technology, dubbed ψ-seq, a team of Whitehead Institute and Broad Institute researchers collaborated on a comprehensive, high-resolution mapping of ψ sites that confirms that pseudouridylation does indeed occur naturally in mRNA. This somewhat surprising finding and the novel approach that led to it were revealed online on September 13, 2014 in Cell.

November 26th

Study Reveals Basis of Key Immune Protein's Two-Faced Role; Identification of TIM-3’s Partner May Stimulate Therapeutic Development

A Brigham and Women's Hospital (BWH)-led team has identified a long-sought-after partner for a key immune protein, called TIM-3 (image), that helps explain TIM-3’s two-faced role in the immune system -- sometimes dampening it, other times stimulating it. TIM-3 is T-cell immunoglobulin mucin-3. It negatively regulates Th1 responses and affects macrophage activation. This newly identified partner of TIM-3 not only sheds light on the inner workings of the immune system in diseases such as HIV, autoimmunity, and cancer, but also provides a critical path toward the development of novel treatments that target TIM-3. The research findings were publishe online on October 26, 2014 in Nature. "There has been a lot of confusion around TIM-3 -- how does it both inhibit and activate the immune system," said Dr. Richard Blumberg, chief of the Division of Gastroenterology, Hepatology, and Endoscopy at BWH and senior author of the paper. "This is a crucial question because TIM-3 has been recognized as an important drug target, but nobody really understands exactly how to approach it because of this Janus-like property." The interest in TIM-3 as a drug target stems largely from its inhibitory role, particularly in cancer. When immune cells are stimulated over long periods of time, they switch on signals, such as TIM-3, that help them dial down their own activity. This chronically activated state, termed "exhaustion," is an immunological hallmark of chronic viral infections, such as HIV. It is also common in cancer. If there were a way to block TIM-3 pharmacologically, it could unleash the immune system, freeing it to attack tumors. Despite this interest, the details of how TIM-3 works have been unclear -- until now. Dr.

November 25th

Link Found Between Transcription and Disease-Causing DNA Repeat Expansions

Researchers in human genetics have known that long nucleotide repeats in DNA lead to instability of the genome and ultimately to human hereditary diseases such as Freidreich's ataxia and Huntington's disease. Scientists have believed that the lengthening of those repeats occurs during DNA replication when cells divide or when the cellular DNA repair machinery gets activated. Recently, however, it became apparent that yet another process called transcription (see image), which is copying the information from DNA into RNA, could also been involved. A Tufts University study published online on November 20, 2014 in Cell Reports by a research team led by Dr. Sergei Mirkin, the White Family Professor of Biology at the Tufts School of Arts and Sciences, along with former graduate student Dr. Kartick Shah and graduate students Ryan McGuity and Vera Egorova, explores the relationship between transcription and the expansions of DNA repeats. It concludes that the active transcriptional state of a DNA segment containing a DNA repeat predisposes it for expansions. "There are a great many simple repetitive motifs in our DNA, such as GAAGAAGAA or CGGCGGCGG," says Dr. Mirkin. "They are stable and cause no harm if they stay short. Occasionally, however, they start lengthening compulsively, and these uncontrollable expansions lead to dramatic changes in genome stability, gene expression, which can lead to human disease." In their study, the researchers used baker's yeast to monitor the progress and the fundamental genetic machineries for transcription, replication, and repair in genome functioning. "The beauty of the yeast system is that it provides one with a practically unlimited arsenal of tools to study the mechanisms of genome functioning," says Dr.