Syndicate content

Archive - Aug 18, 2015

Early, Out-of-Sequence Exposure to Inflammatory Cytokines Paralyzes CD4 T-Cells; Surprising Finding May Engender More Effective Cancer Immunotherapies, Better Drugs for Autoimmune Conditions, New Ways to Speed Sepsis Recovery

In a discovery that is likely to rewrite immunology text books, researchers at the University of California (UC) Davis have found that early exposure to inflammatory cytokines, such as interleukin 2, can "paralyze" CD4 T cells, immune components that help orchestrate the body's response to pathogens and other invaders. This mechanism may act as a firewall, shutting down the immune response before it gets out of hand. However, from a clinical standpoint, this discovery could lead to more effective cancer immunotherapies, better drugs for autoimmune conditions, and new ways to expedite recovery from sepsis. The research was published in the August 18, 2015 issue of the journal Immunity. The article is titled “Out-of-Sequence Signal 3 Paralyzes Primary CD4+ T-Cell-Dependent Immunity.” "There's a three-signal process to activate T cells, of which each component is essential for proper activation," said first author Dr. Gail Sckisel, a post-doctoral fellow. "But no one had really looked at what happens if they are delivered out of sequence. If the third signal - cytokines - is given prematurely, it basically paralyzes CD4 T cells." To be activated, T cells must first recognize an antigen, receive appropriate co-stimulatory signals, and then encounter inflammatory cytokines to expand the immune response. Until now, no one realized that sending the third signal early - as is done with some immunotherapies - could actually hamper overall immunity. "These stimulatory immunotherapies are designed to activate the immune system," said Dr. Sckisel, "but considering how T cells respond, that approach could damage a patient's ability to fight off pathogens.

Combination of Two Serum Biomarkers (Diacetyl Spermine & Pro-SFTPB) Can Identify 80% of Early-Stage Lung Cancer (NSCLC)

Despite decades of warnings about smoking, lung cancer is still the second-most common cancer and the leading cause of death from cancer in the U.S. Patients are often diagnosed only when their disease is already at an advanced stage and difficult to treat. Researchers at the West Coast Metabolomics Center at the University of California (UC) Davis are trying to change that, by identifying biomarkers that could be the basis of early tests for lung cancer. "Early diagnosis is the key to fighting lung cancer," said Dr. Oliver Fiehn, Director of the Metabolomics Center and a Professor of Molecular and Cellular Biology at UC Davis. Lung cancer can be diagnosed early with regular low-dose CT (computed tomography) scans of people at risk. But these tests are very expensive, and also involve exposing patients to X-ray radiation. Instead, Dr. Fiehn, project scientist Dr. William Wikoff, and colleagues set out to look for biomarkers of developing lung cancer in blood from patients. Dr. Fiehn's lab specializes in "metabolomics," an approach that involves analyzing all the biochemical products of metabolism in cells and tissues at the same time. Like other "-omics" approaches, it's made possible by new technology and computing power, and it's opening up new ways to understand living processes. To find early biomarkers for lung cancer, the team needed to look at blood samples collected from people who developed the disease, months or years before they were diagnosed. Fortunately, the researchers were able to access samples stored from the CARET clinical trial. The CARET study, which ran from 1985 until it was halted in 1996, attempted to test whether doses of antioxidant vitamins could prevent cancer in heavy smokers and other people at high risk.

Antimicrobial Lipopeptides (AMLPs), Particularly in Micelle Form, May Prove Effective Alternative to Current Antibiotics

Scientists are planning for a future in which superbugs gain the upper hand against our current arsenal of antibiotics. One emerging class of drug candidates, called AMLPs (antimicrobial lipopeptides), shows promise, and an article published in the August 18, 2015 issue of the Biophysical Journal explains why: they selectively kill bacterial cells, while sparing mammalian host cells, by clumping together into microscopic balls that stick to the bacterial membrane--a complex structure that will be slower to mutate and thus resist drugs. "The pressing need for novel antibiotics against resistant strains of bacteria and fungi has become a global medical concern," says senior study author Dr. Alan Grossfield of the University of Rochester Medical Center in New York. "Our new insights into how AMLPs work as groups, rather than individually, could optimize the development of these molecules as a new class of anti-resistance antibiotics." AMLPs could represent a promising alternative to traditional antibiotics. Past studies have shown that these synthetic compounds have potent activity against a range of pathogens and can clear infections in mice. Moreover, AMLPs are less vulnerable to evolved resistance because they disrupt the structure and function of microbial membranes. To evolve drug resistance, the microbes would require many big changes to alter the mixture of lipids composing the membrane. In addition, a variety of critical proteins embedded in the membrane depend on the membrane's current composition of lipids, so membrane changes that would prevent AMLP function would also tend to hinder the function of the bacteria's own membrane proteins. Despite their advantages, progress in developing AMLPs suitable for the clinic has been limited by the lack of a molecular-level understanding of their mode of action.

Commensal Gut Microbes Produce Retinal-Like Protein That Is Likely the Long-Mysterious Trigger for Autoimmune Uveitis, a Major Cause of Human Blindness

One major cause of human blindness is autoimmune uveitis, which is triggered by the activation of T cells, but exactly how and where the T cells become activated in the first place has been a long-standing mystery. A study, published as an open-access “Featured Article” in the August 18, 2015 issue of the journal Immunity, reveals that gut microbes produce a molecule that mimics a retinal protein, which most likely activates the T cells responsible for the disease. The article is titled “Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site." By shedding light on the cause of autoimmune uveitis in mice, the study could contribute to a better understanding of a broad range of autoimmune disorders and pave the way for novel prevention strategies in the future. "Given the huge variety of commensal bacteria, if they can mimic a retinal protein, it is conceivable that they could also mimic other self-proteins that are targets of inappropriate immune responses elsewhere in the body," says senior study author Dr. Rachel Caspi of the National Institutes of Health. "We believe that activation of immune cells by commensal bacteria may be a more common trigger of autoimmune diseases than is currently appreciated." Autoimmune uveitis, which accounts for up to 15% of severe visual handicap in the Western world, affects the working-age population and significantly affects public health. Patients often have detectable immune responses to unique retinal proteins involved in visual function, and these proteins can elicit the disease in animal models.

Allele-Specific RNA-Seq Used to Study Dynamics of Gene Silencing During Normal X-Inactivation

Each cell in a woman’s body (except egg cells) contains two X chromosomes. One of these chromosomes is switched off, in order to maintain appropriate gene dosage compensation with males who are XY. Dr. Hendrik Marks and Dr. Henk Stunnenberg, molecular biologists at Radboud University Nijmegen, Netherlands, together with the group of Dr. Joost Gribnau from Erasmus MC in Rotterdam, Netherlands, have shown the mechanism by which this inactivation is spread over the X chromosome, The scientific journal Genome Biology will publish the final results; and a provisional PDF was posted online on August 3, 2015. The article is titled “‘Dynamics of Gene Silencing During X Inactivation Using Allele-Specific RNA-Seq.” In terms of sex chromosomes, men have a single X chromosome, as well as a Y chromosome, whereas women have two copies of the X chromosome. A process called X inactivation makes sure that one of these X chromosomes becomes inactivated in females during early embryonic development. A random process determines which of the two is switched off. A nice example of X inactivation can be observed in the fur of female tortoiseshell and calico cats. The gene for fur coloration resides on the X chromosome, while each of the two X chromosomes codes for a different color: black or orange. In an orange “patch,” only the X chromosome encoding the orange color is active, while in the black “patches,” only the X chromosome encoding the black colour is active. During normal human embryo development, X inactivation in females takes place at a very early stage. Others had previously discovered that the molecule “Xist” is key during X inactivation. In order to further study this process, Dr. Marks and his colleagues used embryonic stem cells as a model system to study X inactivation.

New Work Raises Questions about Origins of Early Evolution of Flowering Plants

Indiana University (IU) paleobotanist Dr. David Dilcher and colleagues in Europe have identified a 125 million- to 130 million-year-old freshwater plant as one of earliest flowering plants on Earth. The finding, reported online on August 17, 2015 in PNAS, represents a major change in the presumed form of one of the planet's earliest flowers, known as angiosperms. The article is titled “Montsechia, an ancient aquatic angiosperm.” "This discovery raises significant questions about the early evolutionary history of flowering plants, as well as the role of these plants in the evolution of other plant and animal life," said Dr. Dilcher, an Emeritus Professor in the IU Bloomington College of Arts and Sciences' Department of Geological Sciences. The aquatic plant, Montsechia vidalii, once grew abundantly in freshwater lakes in what are now mountainous regions in Spain. Fossils of the plant were first discovered more than 100 years ago in the limestone deposits of the Iberian Range in central Spain and in the Montsec Range of the Pyrenees, near the Spain's border with France. Also previously proposed as one of the earliest flowers is Archaefructus sinensis, an aquatic plant found in China. "A 'first flower' is technically a myth, like the 'first human,'" said Dr. Dilcher, an internationally recognized expert on angiosperm anatomy and morphology, who has studied the rise and spread of flowering plants for decades. "But based on this new analysis, we know now that Montsechia is contemporaneous, if not more ancient, than Archaefructus." He also asserted that the fossils used in the study were "poorly understood and even misinterpreted" during previous analyses. "The reinterpretation of these fossils provides a fascinating new perspective on a major mystery in plant biology," said Dr. Donald H.

Dr. Amanda Paulovich Wins 2015 “Distinguished Achievement in Proteomic Sciences” Award for Work on MRM-MS Technology to Detect Multiple Proteins Simultaneously; New Technology Advances Clinical Precision Medicine

On August 13, 2015, it was announced that The Human Proteome Organization had named Amanda Paulovich, M.D., Ph.D., as the winner of its 2015 Distinguished Achievement in Proteomic Sciences Award. “This is a great honor and a testament to the hard work of my interdisciplinary team over the past 12 years. It is really a team award,” said Dr. Paulovich, who is a member of Fred Hutchinson Cancer Research Center’s Clinical Research Division, Director of the Hutch’s Early Detection Initiative, and an Associate Professor in the Department of Medicine/Division of Oncology at the University of Washington School of Medicine in Seattle, Washington. The award recognizes a scientist for distinguished scientific achievements in the field of proteomics. It will be presented during the HUPO 2015 Vancouver CongressSeptember 27-September 30, 2015 (https://www.hupo.org/events/hupo-14th-annual-world-congress-vancouver-20...), the organization’s 14th annual worldwide meeting. Dr, Paulovich and her lab have played a major role in the development of an efficient, high-powered, precise method to detect and measure proteins in biological samples, called multiple reaction monitoring mass spectrometry *(MRM-MS). Named “Method of the Year” for 2012 by Nature Methods (http://www.nature.com/nmeth/journal/v10/n1/full/nmeth.2329.html), MRM-based proteomic assays have the potential to overcome a serious problem in biomedical research, i.e., a lack of reliable, standardizable tests for studying human proteins. Proteins carry out most biological functions in the body – including driving cancer –and are the targets of most drugs.