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Archive - 2012

February 22nd

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.

Nervous System Wiring May Rely on Just a Handful of Genes and Proteins

Researchers at the Salk Institute have discovered a startling feature of early brain development that helps to explain how complex neuron wiring patterns are programmed using just a handful of critical genes. The findings, published in the February 3, 2012 issue of Cell, may help scientists develop new therapies for neurological disorders, such as amyotrophic lateral sclerosis (ALS), and provide insight into certain cancers. The Salk researchers discovered that only a few proteins on the leading edge of a motor neuron's axon - its outgoing electrical "wire" - and within the extracellular soup it travels through, guide the nerve as it emerges from the spinal cord. These molecules can attract or repel the axon, depending on the long and winding path it must take to finally connect with its target muscle. "The budding neuron has to detect the local environment it is growing through and decide where it is, and whether to grow straight, move to the left or right, or stop," says the study's senior investigator, Dr. Sam Pfaff, a professor in Salk's Gene Expression Laboratory and a Howard Hughes Medical Institute investigator. "It does this by mixing and matching just a handful of protein products to create complexes that tell a growing neuron which way to go, in the same way that a car uses the GPS signals it receives to guide it through an unfamiliar city," he says. The brain contains millions of times the number of neuron connections than the number of genes found in the DNA of brain cells. This is one of the first studies to try and understand how a growing neuron integrates many different pieces of information in order to navigate to its eventual target and make a functional connection.

February 10th

Drug Halts Organ Damage in Rare Inflammatory Genetic Disorder

A new study shows that Kineret (anakinra), a medication approved for the treatment of rheumatoid arthritis, is effective in stopping the progression of organ damage in people with neonatal-onset multisystem inflammatory disease (NOMID). This rare and debilitating genetic disorder causes persistent inflammation and ongoing tissue damage. The research was performed by scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health. NOMID affects numerous organs and body systems, including the skin, joints, eyes, and central nervous system. The first sign of the disease is often a rash that develops within the first weeks of life. Other problems, including fever, meningitis, joint damage, vision and hearing loss, and mental retardation, can follow. Kineret, one of a relatively new class of drugs known as biologic response modifiers or biologics, blocks the activity of interleukin-1 (IL-1), a protein made by cells of the immune system. IL-1 is overproduced in NOMID and a number of other diseases, leading to damaging inflammation. Previous work by the same NIAMS group showed that blocking IL-1 was effective in relieving symptoms of NOMID. However, this is the first study to show that Kineret works over the long-term and, at higher doses, can also control damage that often results in vision and hearing loss, and brain lesions. “Inflammation prolonged over many years will eventually cause irreversible damage and loss of function,” said lead author Dr. Raphaela Goldbach-Mansky of the NIAMS Translational Autoinflammatory Disease Section. For example, inflammation of the cochlea — a tiny structure of the inner ear — was found to be responsible for hearing loss in people with NOMID.

Molecular Profiling Reveals Differences Between Primary and Recurrent Ovarian Cancers

There is a need to analyze tumor specimens at the time of ovarian cancer recurrence, according to a new study published in the February 2012 issue of Molecular Cancer Therapeutics. Researchers used a diagnostic technology called molecular profiling to examine the differences in the molecular characteristics of primary and recurrent ovarian tumors and found significant changes for some biomarkers. This is the first study that examined potential differences in a broad biomarker panel in patient-matched primary versus recurrent ovarian cancers and underscores the importance of analyzing the most current tumor tissue in order to make the most informed decisions about treatment for recurrence. Ovarian cancer is the most deadly of gynecological cancers, and is the fifth leading cause of cancer-related death among women in the United States. Treatment for recurrent ovarian cancer often follows a trial-and-error approach in spite of molecular profiling technologies available to inform treatment selection. Profiling technologies may be utilized at the time of ovarian cancer recurrence, but the tumor specimens that are analyzed are most often those obtained at initial diagnosis. This profiling of the primary tumor does not take into account changes that occur in recurrent tumors, which may have enabled their survival after chemotherapy treatment. Lead author Dr. Deb Zajchowski, Scientific Director of The Clearity Foundation, says, "These results highlight additional challenges for the treatment of recurrent ovarian cancer. The study helps us appreciate the degree to which tumor characteristics that may be useful for making treatment decisions may change over the course of this disease." Dr. Zajchowski, Clearity Scientific Advisor Dr. Beth Y.

Approved Cancer Drug Quickly Reverses Alzheimer's Symptoms in Mice

Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer's disease. The researchers' findings, published online on February 9, 2012 in Science, show that use of a drug in mice appears to quickly reverse the pathological, cognitive, and memory deficits caused by the onset of Alzheimer's. The results point to the significant potential that the medication, bexarotene, has to help the roughly 5.4 million Americans suffering from the progressive brain disease. Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer's disease, and the results were more than promising. Alzheimer's disease arises in large part from the body's inability to clear naturally-occurring amyloid beta from the brain. In 2008, Case Western Reserve researcher Dr. Gary Landreth, professor of neurosciences, discovered that the main cholesterol carrier in the brain, apolipoprotein E (ApoE), facilitated the clearance of the amyloid beta proteins. Dr. Landreth is the senior author of this Science study. Dr. Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced. In particular, the researchers were struck by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of Alzheimer's disease.