Syndicate content

Archive - Mar 2015

March 29th

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.

March 28th

Preliminary Results Indicate Roseroot May Be Beneficial Treatment Option for Major Depressive Disorder

Rhodiola rosea (R. rosea) (photo), or roseroot, may be a beneficial treatment option for major depressive disorder (MDD), according to results of a study published in the March 15, 2015 issue of the journal Phytomedicine> The study was led by Jun J. Mao, M.D., M.S.C.E., Associate Professor of Family Medicine, Community Health and Epidemiology and colleagues at the Perelman School of Medicine of University of Pennsylvania. The proof of concept trial study is the first randomized, double-blind, placebo-controlled, comparison trial of oral R. rosea extract versus the conventional antidepressant therapy sertraline for mild to moderate major depressive disorder. Depression is one of the most common and debilitating psychiatric conditions, afflicting more than 19 million Americans each year, 70 percent of whom do not fully respond to initial therapy. Costs of conventional antidepressants and their sometimes substantial side effects often result in a patient discontinuing use prematurely. Others opt to try natural products or supplements instead. All of the study's 57 adult participants, enrolled from December 2010 and April 2013, had a DSM IV Axis 1 diagnosis of MDD, meaning they exhibited two or more major depressive episodes, depressed mood and/or loss of interest or pleasure in life activities for at least 2 weeks, as well as symptoms including significant unintentional weight loss or gain, insomnia or sleeping too much, fatigue, and diminished ability to think or concentrate, and recurrent thoughts of death. The participants received 12 weeks of standardized R. rosea extract, sertraline, or placebo. Changes over time in Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and Clinical Global Impression (CGI) change scores were measured among groups.

Ebola Whole Virus Vaccine Effective & Save in Macaques, UW-Madison Study Shows

An Ebola whole virus vaccine, constructed using a novel experimental platform, has been shown to effectively protect monkeys exposed to the often fatal virus. The vaccine, described online on March 26, 2015 in an article in Science, was developed by a group led by Dr. Yoshihiro Kawaoka, a University of Wisconsin-Madison expert on avian influenza, Ebola, and other viruses of medical importance. The vaccine differs from other Ebola vaccines because as an inactivated whole virus vaccine, it primes the host immune system with the full complement of Ebola viral proteins and genes, potentially conferring greater protection. "In terms of efficacy, this affords excellent protection," explains Dr. Kawaoka, a Professor of Pathobiological Sciences in the UW-Madison School of Veterinary Medicine and who also holds a faculty appointment at the University of Tokyo. "It is also a very safe vaccine." The vaccine was constructed on an experimental platform first devised in 2008 by Dr. Peter Halfmann, a research scientist in Dr. Kawaoka's lab. The system allows researchers to safely work with the virus thanks to the deletion of a key gene known as VP30, which the Ebola virus uses to make a protein required for it to reproduce in host cells. Ebola virus has only eight genes and, like most viruses, depends on the molecular machinery of host cells to grow and become infectious.

The Secret Life of Giant Pandas

Reclusive giant pandas fascinate the world, yet precious little is known about how they spend their time in the Chinese bamboo forests--until now. A team of Michigan State University (MSU) researchers who have been electronically stalking five pandas in the wild, courtesy of rare GPS collars, have finished crunching months of data and published some panda surprises online on March 27, 2015 in the Journal of Mammalogy. "Pandas are such an elusive species and it's very hard to observe them in wild, so we haven't had a good picture of where they are from one day to the next," said Vanessa Hull, Ph.D., a research associate at MSU's Center for Systems Integration and Sustainability (CSIS). Dr. Jindong Zhang, a co-author on the paper and postdoctoral researcher at CSIS continues "This was a great opportunity to get a peek into the panda's secretive society that has been closed off to us in the past." Dr. Hull adds, "Once we got all the data in the computer we could see where they go and map it. It was so fascinating to sit down and watch their whole year unfold before you like a little window into their world." The five pandas - three female adults named Pan Pan, Mei Mei, and Zhong Zhong, a young female named Long Long and a male named Chuan Chuan - were captured, collared, and tracked from 2010 to 2012, in the Wolong Nature Reserve in southwest China. The Chinese government is protective of its endangered pandas and for more than a decade banned putting GPS collars on them. While a handful of studies have tracked some, this is one of the first times technology has been used that provided more detail on the pandas' movements and how they interact with one another over time. One of the biggest surprises was that the pandas seemed to spend significant time together sometimes.