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Archive - Mar 29, 2015

Modified Polio Virus Used in Fight Against Glioblastomas, 60 Minutes Reports

Dr. Matthias Gromeier's original notion that polio virus (image) might be used to kill cancerous tumors was met for some time with much disdain. But now, two decades later, use of the virus known for crippling and killing millions is showing promise against one of the deadliest forms of cancer - glioblastoma brain tumors. In a 60 Minutes story airing on CBS the evening of March 29, 2015, reporter Scott Pelley meets two patients participating in the phase 1 clinical trial of the polio-virus-based anti-glioblastoma therapy, who have been declared cancer-free by doctors. "I got a range of responses, from crazy to you're lying... most people just thought it was too dangerous," said Dr. Gromeier, an Associate Professor of Surgery and Associate Professor in Molecular Genetics and Microbiology at Duke, where he has been for the last 15 years, when he started pushing his idea to attack tumors with the polio virus. One of those naysayers was Dr. Henry Friedman, a neuro-oncologist who is now the Deputy Director of the Brain Tumor Center at Duke University where the phase 1 clinical trial of the polio-virus therapy is now being carried out. "I thought he was nuts," Dr. Friedman told Pelley. "I really thought he was using a weapon that produced paralysis." That was 15 years ago. Today, after research, animal trials, and now this human clinical trial, Dr. Friedman is more than optimistic. "This, to me, is the most promising therapy I have seen in my career, period," said Dr. Friedman who has been researching a cure for glioblastoma for more than 30 years. Dr. Gromeier's research yielded a genetically modified polio virus that could be used safely in animals and now, it seems, in humans.

Triple-Negative Breast Cancer Appears to Be Two Different Diseases; Very Serious One Starts from Stem Cells, More Benign One Starts from More Specialized Cells; High Levels of ID4 Associated with Very Poor Prognosis

Australian researchers have found that so-called “triple-negative breast cancers” are two distinct diseases that likely originate from different cell types. This helps explain why survival prospects for women with the diagnosis tend to be either very good or very bad. The Sydney-based research team has found a gene that drives the aggressive disease, and hopes to find a way to “switch it off.” The aggressive form of triple-negative breast cancer appears to arise from stem cells, while the more benign form appears to arise from specialized cells. Stem cells have many of the same features as cancers. They are plastic and flexible, and have the ability to proliferate and spread into other tissues - deadly traits in cancers. Previous studies have shown that breast stem cells are needed for breast growth and development during puberty and pregnancy, although how they evolve from stem cells into specialist cells has been unclear. The new study has shown that a gene known as “inhibitor of differentiation 4” (ID4) determines whether a stem cell remains a stem cell, or whether it differentiates into a specialist cell. Notably, when the high levels of ID4 in a stem cell are “switched off,” other genes that drive cell specialization are “switched on.” Dr. Alex Swarbrick and Dr. Simon Junankar from Sydney's Garvan Institute of Medical Research spearheaded this large interdisciplinary study, which employed an ID4GFP knock-in reporter mouse and single-cell transcriptomics to show that ID4 marks a stem-cell-enriched subset of the mammary basal cell population. The study’s main finding, that ID4 not only “marks,” but appears to control, the highly aggressive form of triple negative breast cancer was published online on March 27, 2015 in Nature Communications.

deCODE Shows Power of Iceland Population Sequencing

deCODE Genetics, a global leader in analyzing and understanding the human genome, has published online, on March 25, 2015, in Nature Genetics, four landmark papers built on whole-genome sequence data from more than 100,000 people from across the country of Iceland. The studies, written by a team of deCODE scientists, when taken together, present the most detailed portrait of a population yet assembled using the latest technology for reading DNA. "This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species and for contributing to new means of diagnosing, treating, and preventing disease," said Kari Stefansson, M.D., Founder and CEO of deCODE, and senior author on the four Nature Genetics papers. "It also shows how a small population such as ours, with the generous participation of the majority of its citizens, can advance science and medicine worldwide. In that sense, this is very much more than a molecular national ‘selfie.’ We're contributing to important tools for making more accurate diagnostics for rare diseases; finding new risk factors and potential drug targets for diseases like Alzheimer's; and even showing how the Y chromosome, a loner in the paired world of our genome, repairs itself as it passes from father to son. Other countries are now preparing to undertake their own large-scale sequencing projects, and I would tell them the rewards are great," Dr. Stefansson concluded. The four Nature Genetics papers and their highlights are described below.

Study Demonstrates Feedback Loop Between Brown Fat and the Brain

Brown fat tissue communicates with the brain through sensory nerves, possibly sharing information that is important for fighting obesity, such as how much fat we have and how much fat we've lost, according to researchers at Georgia State University. The findings, published in the February 4, 2015 issue of The Journal of Neuroscience, help to describe the conversation that takes place between the brain and brown fat tissue while brown fat is generating heat. The article is titled “Brown Adipose Tissue Has Sympathetic-Sensory Feedback Circuits.” The experiments in this work were carried out in Siberian hamsters. Brown fat is considered "good fat" or "healthy fat" because it burns calories to help generate heat for our bodies and expend energy, while the far-more-abundant white fat stores energy for later use and can increase the risk for health issues, such as diabetes and heart disease. Studies have suggested that brown fat plays a significant role in someone having the capability to burn more energy, becoming a tool to stay trim and fight obesity. Pharmaceutical companies are trying to target brown fat and learn how to further activate it, said John Garretson, second author on the study and a doctoral student in the Neuroscience Institute and Center for Obesity Reversal at Georgia State. The current study found that when brown fat tissue was activated with a drug that mimics the sympathetic nervous system messages that normally come from the brain, the brown fat talked back to the brain by activating sensory nerves. The sensory nerves from brown fat increased their activity in response to direct chemical activation and heat generation. "This is the first time that the function of sensory nerves from brown fat has been examined," Garretson said.

Higher Methylation of Fragile X Gene in Certain Premutation Women Is Associated with Increased Frequency of Depression, Social Anxiety, and Executive Functioning Problems; Blood Test for Methylation May Permit Identification of This At-Risk Group

A blood test may shed new light on Fragile X syndrome related disorders in women, according to a new study published online on March 25, 2015 in Neurology, the medical journal of the American Academy of Neurology. The title of the article is” Novel Methylation Markers of the Dysexecutive-Psychiatric Phenotype inFMR1 Premutation Women.” Fragile X is the most common inherited form of intellectual disability and the most frequent genetic cause of autism. Fragile X, which is caused by a mutation in a single gene on the X chromosome, affects about 1 in 4,000 men and 1 in 6,000 women. [The mutation causes the X chromosome to appear fragile upon cytogenetic examination—see photo—hence, the name.] Even more common are Fragile X carriers of a lesser change in the Fragile X gene called a premutation, occurring in 1 in 450 men and 1 in 150 women. Fragile X premutation carriers have normal intellect, but some can develop physical symptoms over time. They are also more likely to develop social anxiety and depression. In the current study, researchers compared 35 women who had the premutation to 35 women who did not have this genetic change. The participants were given tests of their brains' executive functioning skills, such as inhibition and selective attention, and rated themselves on scales for depression and social anxiety. They also had blood tests to measure the amount of methylation in the Fragile X gene. Methylation adds methyl groups to some of the DNA, which inactivates that part of the X chromosome. Methylation is one type of so-called epigenetic changes, non-DNA alterations in genes during the lifetime that affect their expression.

Big Data Analysis Sheds Light on Yin & Yang of Gephyrin Gene, a Master Regulator of Message Transmission in the Brain; New Approach May Also Prove Useful in Analysis of Complex Diseases Involving Interactions of Multiple Genes

Big data: It's a term we read and hear about often, but is hard to grasp. Computer scientists at Washington University in St. Louis' (WUSL) School of Engineering & Applied Science tackled some big data about an important protein and discovered its connection in human history as well as clues about its possible role in complex neurological diseases. Through a novel method of analyzing these big data, Sharlee Climer, Ph.D., Research Assistant Professor in Computer Science, and Weixiong Zhang, Ph.D., Professor of Computer Science and of Genetics at the School of Medicine, discovered a region encompassing the gephyrin gene on chromosome 14 that underwent rapid evolution after splitting in two completely opposite directions thousands of years ago. Those opposite directions, known as yin and yang, are still strongly evident across different populations of people around the world today. The results of the research, carried out together with Alan Templeton, Ph.D., the Charles Rebstock Professor Emeritus in the Department of Biology in the College of Arts & Sciences at WUSL, was published online on March 27, 2015 in Nature Communications. The article is titled “Human Gephyrin Is Encompassed within Giant Functional Noncoding Yin-Yang Sequences.” The gephyrin protein is a master regulator of receptors in the brain that transmit messages. Malfunction of the protein has been associated with epilepsy, Alzheimer's disease, schizophrenia, and other neurological diseases. Additionally, without gephyrin, our bodies are unable to synthesize an essential trace nutrient (molybdenum co-factor).

How NSF/α-SNAP Disassembles the SNARE Complex in Intracellular Vesicular Trafficking

In 2013, Drs. James E. Rothman, Randy W. Schekman, and Thomas C. Südhof shared the Nobel Prize in Physiology or Medicine for their discoveries of molecular machineries for vesicle trafficking, a major transport system in cells for maintaining cellular processes. Vesicle traffic acts as a kind of "home-delivery service" in cells. Vesicles package and deliver materials such as proteins and hormones from one cell organelle to another. The vesicle releases its contents by fusing with the target organelle's membrane. One example of vesicle traffic is in neuronal communications, where neurotransmitters are released from a neuron. Some of the key proteins for vesicle traffic discovered by the Nobel Prize winners were N-ethylmaleimide-sensitive factor (NSF), alpha-soluble NSF attachment protein (α-SNAP), and soluble SNAP receptors (SNAREs). SNARE proteins are known as the minimal machinery for membrane fusion. To induce membrane fusion, the proteins combine to form a SNARE complex in a four-helix bundle, and NSF and α-SNAP disassemble the SNARE complex for reuse. In particular, NSF can bind an energy source molecule, ATP, and the ATP-bound NSF develops internal tension via cleavage of ATP. This process is used to exert great force on SNARE complexes, eventually pulling them apart. However, although about 30 years have passed since the Nobel Prize winners' actual discovery, how NSF/α-SNAP disassemble the SNARE complex has remained a mystery to scientists due to a lack the appropriate investigative methodology. Now, in article published in the March 27, 2015 issue of Science, a research team, led by Dr. Tae-Young Yoon of the Department of Physics at the Korea Advanced Institute of Science and Technology (KAIST) and Dr.