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Archive - Feb 2012

Date

February 27th

Study of New Cell May Lead to New Treatments for Asthma, Other Allergies

A collaboration between scientists at Trinity College Dublin (TCD) and in the United Kingdom has identified new processes that lead to the development of a novel cell (the nuocyte) implicated in allergies. The discovery has the potential to spawn new strategies to treat asthma and other allergic diseases. The research findings were published in the March 2012 issue of Nature Immunology. The work was performed by Professor Padraic Fallon, Science Foundation Ireland Stokes Professor of Translational Immunology of TCD's School of Medicine, Dr. Andrew McKenzie of the Medical Research Council Laboratory for Molecular Biology in Cambridge, UK, and colleagues. The number of people with allergic disease, such as asthma and atopic dermatitis, is increasing globally with Irish children having the fourth highest incidence of asthma in the world. A major area of research in developing new strategies to treat allergic diseases is directed towards increasing understanding of the processes and cells involved in causing allergic inflammation. Professor Fallon and colleagues previously discovered a new white blood cell (the nuocyte) that initiates the early generation of the immune responses that can lead to asthma or other allergic conditions. In the current study, a new pathway for the development of nuocytes was identified and a transcription factor, RORalpha, was shown to be critical for both the generation of nuocytes and of allergic-like inflammation. This new finding identifies targets for allergic diseases that could be developed into new therapeutic strategies. [Press release] [Nature Immunology abstract]

Research Refutes Popular Hypothesis of Multiple Sclerosis Triggering Mechanism

Millions of adults suffer from the incurable disease multiple sclerosis (MS). It is relatively certain that MS is an autoimmune disease in which the body's own defense cells attack the myelin in the brain and spinal cord. Myelin enwraps the nerve cells and is important for their function of transmitting stimuli as electrical signals. There are numerous unconfirmed hypotheses on the development of MS, one of which has now been refuted by the neuroimmunologists in their current research: The death of oligodendrocytes, as the cells that produce the myelin sheath are called, does not trigger MS. With their research, published February 26, 2012 in Nature Neuroscience, the scientists disprove the so-called "neurodegenerative hypothesis," which was based on observations that certain patients exhibited characteristic myelin damage without a discernable immune attack. In the popular hypothesis, the scientists assume that MS-triggering myelin damage occurs without the involvement of the immune system. In this scenario, the immune response against myelin would be the result – and not the cause – of this pathogenic process. The aim of the current research project was to confirm or disprove this hypothesis based on a new mouse model. Using genetic tricks, the researchers induced myelin defects without alerting the immune defense. "At the beginning of our study, we found myelin damage that strongly resembled the previous observations in MS patients," explains Dr. Burkhard Becher, a professor at the University of Zurich. "However, not once were we able to observe an MS-like autoimmune disease." In order to ascertain whether an active immune defense causes the disease based on a combination of an infection and myelin damage, the researchers conducted a variety of further experiments – without success.

February 23rd

Human Y Chromosome Not Headed to Extinction

If you were to discover that a fundamental component of human biology has survived virtually intact for the past 25 million years, you'd probably be quite confident in saying that it is here to stay. Such is the case for a team of Whitehead Institute scientists, whose latest research on the evolution of the human Y chromosome confirms that the Y—despite arguments to the contrary—has a long, healthy future ahead of it. Proponents of the so-called “rotting Y” theory have been predicting the eventual extinction of the Y chromosome since it was first discovered that the Y has lost hundreds of genes over the past 300 million years. The rotting Y theorists have assumed this trend is ongoing, concluding that inevitably, the Y will one day be utterly devoid of its genetic content. Over the past decade, Whitehead Institute Director Dr. David Page and his lab have steadily been churning out research that should have permanently debunked the rotting Y theory, but to no avail. "For the past 10 years, the one dominant storyline in public discourse about the Y is that it is disappearing," says Dr. Page. "Putting aside the question of whether this ever had a sound scientific basis, the story went viral—fast—and has stayed viral. I can't give a talk without being asked about the disappearing Y. This idea has been so pervasive that it has kept us from moving on to address the really important questions about the Y." To Dr. Page, this latest research represents checkmate in the chess match he's been drawn into against the "rotting Y" theorists. Members of his lab have dealt their fatal blow by sequencing the Y chromosome of the rhesus macaque—an Old World monkey whose evolutionary path diverged from that of humans some 25 million years ago—and comparing it with the sequences of the human and chimpanzee Y chromosomes.

February 22nd

Study Suggests Novel Genetic Model of Skin Cancer

The University of Kentucky (UK) has announced that Dr. Daret St. Clair, the James Graham Brown Endowed Chair and professor of toxicology, has published the first comprehensive study that provides insight into the relationship between two types of suppressors in cancerous tumors. The results will enhance the understanding of transcriptional mechanisms in carcinogenesis. The study was supported by a National Cancer Institute research grant and was published in the November 1, 2011 issue of Cancer Research. Dr. St. Clair and her team generated transgenic mice expressing a luciferase reporter gene under the control of human MnSOD promoter-enhancer elements and investigated the changes of MnSOD transcription using the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-l3-acetate (TPA) multistage skin carcinogenesis model. Manganese superoxide dismutase (MnSOD) plays a critical role in the survival of aerobic life, and its abnormal expression has been implicated in carcinogenesis and tumor resistance to therapy. Despite extensive studies in MnSOD regulation and its role in cancer, when and how the alteration of MnSOD expression occurs during the process of tumor development in vivo are unknown. The current results show that MnSOD expression was suppressed at a very early stage, but increased at late stages of skin carcinogenesis. The suppression and subsequent restoration of MnSOD expression were mediated by two transcription factors, Sp1 and p53. Exposure to DMBA and TPA activated p53 and decreased MnSOD expression via p53-mediated suppression of Sp1 binding to the MnSOD promoter in normal appearing skin and benign papillomas. In squamous cell carcinomas, Sp1 binding increased due to loss of functional p53. Dr. St.

Potentially Deadly Fungus Senses Body’s Defenses to Evade Them

Dr. Glen Palmer, Assistant Professor of Microbiology, Immunology & Parasitology at Louisiana State University (LSU) Health Sciences Center New Orleans, was part of an international research team led by Dr. Luigina Romani, at the University of Perugia in Italy, that discovered opportunistic fungi like Candida albicans can sense the immune status of host cells and adapt, evading immune system defenses. Unlike previous studies, this research investigated both sides of the infection equation, as well as the interaction between the fungi and the cells they will invade. The findings were published online on February 21, 2012 in Nature Communications. This study demonstrates that this process is much more elaborate and complex than previously understood. The researchers determined that C. albicans binds to the host immune signaling molecule, interleukin (IL) 17A, which permits the fungus to navigate and tolerate the active immune environment of healthy host tissue, mounting effective countermeasures. IL-17A may also contribute to disease susceptibility by modifying the intrinsic virulence of the fungus. This study provides molecular evidence that by exploiting IL-17A, the fungus not only survives, but can cause disease to develop. "It's a bit like the fungus is listening in to the conversations our immune system is having so it can best determine how to react and survive in our tissues. This may also be a crucial step in determining when this opportunist decides to invade host tissue and cause life-threatening disease in an immunosuppressed patient," notes Dr. Palmer. According to the Centers for Disease Control and Prevention, there are more than 20 species of Candida yeasts that can cause infection in humans, the most common of which is Candida albicans.

February 14th

Advantages of LATE-PCR Technology

BioQuick News recently had the opportunity to speak with Dr. Lawrence Wangh about the novel technology of LATE-PCR (LATE stands for Linear After The Exponential) (see references 1-3 below). Dr. Wangh is professor of biology and director of the Laboratory of Molecular Diagnostics and Global Health at Brandeis University near Boston. Over the past ten years, he and his laboratory colleagues have invented LATE-PCR and a suite of allied technologies. Dr. Wangh said that LATE-PCR is an advanced form of non-symmetric PCR that overcomes many of the limitations of conventional (symmetric and asymmetric) PCR. These limitations are particularly evident in samples containing low numbers of initial targets. LATE-PCR makes efficient use of a limiting primer and an excess primer that together cause the reaction to abruptly switch from efficient production of double-stranded to single-stranded DNA, when the limiting primer is used up. This is of great utility because single-stranded amplicons can be readily probed at end-point over a broad range of temperatures. This, in turn, allows for the use of probes that hybridize to target sequence variants at different temperatures. LATE-PCR assays are further enhanced by use of PrimeSafeTM, a proprietary reagent that suppresses all forms of mis-priming throughout amplification and makes it far easier to build highly multiplexed reactions. In addition, the lab has recently invented ThermalightTM Lights-On/Lights-Off probes that allow several different long target sequences to be scanned for sequence variants, each in a different fluorescent color. Dr. Wangh said that LATE-PCR makes it possible to build highly informative cost-effective, closed-tube assays for detection of mutations in hundreds of nucleotides.

February 13th

Antibodies to Intracellular Cancer Antigens Can Enhance Anti-Cancer Immunity

An international team of scientists in Japan, Switzerland, and the United States has confirmed that combining chemotherapy and immunotherapy in cancer treatment enhances the immune system's ability to find and eliminate cancer cells, even when the cancer-associated proteins targeted by the immune system are hidden behind the cancer cell membrane. In a study published online on February 8, 2012 in Cancer Research, the scientists show that antibodies, which have been successful in treating certain types of cancers, can effectively reach elusive intracellular targets, delaying tumor growth and prolonging survival when combined with chemotherapy. "The study provides proof-of-principle for a powerful new strategy that may greatly expand the arsenal of potential targets for cancer drug development and that could be broadly applicable to many different cancer types," said Dr. Hiroyoshi Nishikawa, a Cancer Research Institute (CRI)-funded associate professor in the Department of Experimental Immunology at the Immunology Frontier Research Center, Osaka University, and a senior author on the Cancer Research paper. The introduction of antibodies against cancer represents one of the biggest successes of cancer therapy over the past 20 years. These treatments work by targeting markers on the surface of cancer cells, and include the blockbuster therapies Herceptin, which targets the HER2/neu marker on breast cancer cells, and Rituxan, which targets the CD20 marker on B cell lymphoma. The majority of markers that can distinguish cancer cells from normal cells, however, are found exclusively inside cancer cells, where antibodies typically cannot access them.

February 12th

BGI Researchers Discover Extensive RNA Editing in a Human Transcriptome

In a new study published online on February 12, 2012 in Nature Biotechnology, researchers from China’s BGI, the world's largest genomics organization, reported the evidence of extensive RNA editing in a human cell line by analysis of RNA-seq data, demonstrating the need for new robust methods to identify important post-transcriptional editing events. RNA editing is a normal, but not yet fully understood, process in which small nucleotide changes occur after DNA has been transcribed into RNA. It is an integral step in generating diversity and plasticity of cellular RNA signature as a post-transciptional event that recodes hereditary information. RNA editing is an important area in the post-genomic era for its role in determining protein structure and function. It has become increasingly important in genetic research. Last year, a study published in Science (Li et al. Science, May 19, 2011) reported a large number of sequence differences between mRNA and DNA in the human transcriptome. This finding was startling because it implied that there might be a still undiscovered mechanism of 'RNA editing' that could disrupt the central dogma and affect our understanding of genetic variation. However, this view was strongly contested by other scientists because of the technical issue and lack of academic rigor, such as sequencing error or mis-mapping. In this latest study, BGI researchers developed a more rigorous pipeline for approaching these problems and answered some of the concerned questions, which contributed to paving way for the further studies of this field. The researchers obtained the whole-transcriptome data by RNA-seq from a lymphoblastoid cell line of a male Han Chinese individual (YH), whose genome sequence was previously reported as the first diploid genome of Han Chinese.

Anti-Diabetic Medication Can Prevent Long-Term Effects of Maternal Obesity

In a study presented February 11, 2012 at the Society for Maternal-Fetal Medicine's annual meeting, The Pregnancy Meeting ™, in Dallas, Texas, researchers reported findings that show that short therapy with the anti-diabetic medication Pioglitazone can prevent the long-term effects of maternal obesity on offspring. This study, “Pioglitazone Therapy in Offspring Exposed to Maternal Obesity,” is the first step toward the long-term goal of preventing metabolic syndrome and obesity in children secondary to maternal obesity. The data proposes a potential role for drugs that activate peroxisome proliferator-activated receptors in the prevention of metabolic syndrome in adult offspring of obese mothers. "Obesity in children, which is on the rise, predisposes them to lifelong diseases such as diabetes, high lipid levels, hypertension, and cardiac diseases," said Dr. Egle Bytautiene, with The University of Texas Medical Branch, Obstetrics and Gynecology, Galveston, Texas, and one of the study's authors. "A large part of obesity in children is programmed during pregnancy and our study shows that a drug used to treat diabetes in adults can prevent the long-term effects of maternal obesity on the offspring, even when used for a short period of time after birth." Dr. Bytautiene and her colleagues placed mice on a high-fat diet for three months prior to, and during pregnancy. The resulting pups were weaned to a regular diet. Pups were randomly selected to receive Pioglitazone or a placebo. Treatment was given once daily from 10 to 12 weeks of age. Immediately before and after the treatment period, the offspring were weighed, their visceral adipose tissue was evaluated using computed-tomography, blood was collected for fasting glucose and triglyceride analysis, and intraperitoneal glucose tolerance tests were performed.

February 11th

Study Reveals Probable Mechanism Underlying Resveratrol Activity

National Institutes of Health researchers and their colleagues have identified how resveratrol, a naturally occurring chemical found in red wine and other plant products, may confer its health benefits. The authors present evidence that resveratrol does not directly activate sirtuin 1, a protein associated with aging. Rather, the authors found that resveratrol inhibits certain types of proteins known as phosphodiesterases (PDEs), enzymes that help regulate cell energy. These findings may help settle the debate regarding resveratrol's biochemistry and pave the way for resveratrol-based medicines. The chemical has received significant interest from pharmaceutical companies for its potential to combat diabetes, inflammation, and cancer. The study appears in the February 3, 2012 issue of Cell. "Resveratrol has potential as a therapy for diverse diseases such as type 2 diabetes, Alzheimer's disease, and heart disease," said lead study author Dr. Jay H. Chung, chief of the Laboratory of Obesity and Aging Research at the NIH's National Heart, Lung, and Blood Institute. "However, before researchers can transform resveratrol into a safe and effective medicine, they need to know exactly what it targets in cells." Several previous studies suggested that resveratrol's primary target is sirtuin 1. Dr. Chung and colleagues suspected otherwise when they found that resveratrol activity required another protein called AMPK. This would not be the case if resveratrol directly interacted with sirtuin 1. In the current study, the researchers methodically traced out the metabolic activity in cells treated with resveratrol and identified PDE4 in the skeletal muscle as the principal target for the health benefits of resveratrol. By inhibiting PDE4, resveratrol triggers a series of events in a cell, one of which indirectly activates sirtuin 1.