Syndicate content

Archive - Oct 2015

October 11th

3D Structure of Biologically Active DNA Revealed in Unprecedented Detail; Myriad Beautiful & Unexpected Shapes Seen in Dynamic Super-Coiled DNA; Hinges May Make Tightly Wound DNA More Open Than Thought

Researchers at the Baylor College of Medicine (USA) and the University of Leeds (UK) have imaged, in unprecedented detail, the three-dimensional structure of supercoiled DNA, revealing that its shape is much more dynamic than the well-known linear double-helix. Various DNA shapes, including figure-8's, were imaged using a powerful microscopy technique by researchers at Baylor, and then examined using supercomputer simulations run at the University of Leeds. As reported online on October 12, 2015 in an open-access article published in Nature Communications, the simulations also show the dynamic nature of DNA, which constantly wiggles and morphs into different shapes - a far cry from the commonly held idea of a rigid and static double-helix structure. Improving the understanding of what DNA looks like when it is in the cell will help us to design better medicines, such as new antibiotics or more effective cancer chemotherapies, the researchers suggest. "This is because the action of drug molecules relies on them recognizing a specific molecular shape - much like a key fits a particular lock," said Dr. Sarah Harris from the School of Physics and Astronomy at the University of Leeds, who led the computer simulation research side of the study. The Nature Communications article is titled “'The Structural Diversity of Supercoiled DNA.” The double-helix shape has a firm place in the public's collective consciousness. It is referenced in popular culture and often features in art and design. But the shape of DNA isn't always that simple. Dr. Harris said: "When Watson and Crick described the DNA double-helix, they were looking at a tiny part of a real genome, only about one turn of the double helix. This is about 12 DNA base pairs, which are the building blocks of DNA that form the rungs of the helical ladder.

Key Virulence Factors of Human Malaria Parasite Much More Ancient Than Thought; Intact Gene Segments Were Exchanged and Evolved in Plasmodium Sub-Genus in Apes Before Emergence of Human Malaria Parasiste (P. falciparum)

The malaria parasite (Plasmodium falciparum) (image) molecules associated with severe disease and death--those that allow the parasite to escape recognition by the immune system--have been shown to share key gene segments with chimp and gorilla malaria parasites, which are separated by several millions of years of evolution, according to a new study led by researchers at the Harvard T.H. Chan School of Public Health. This new information about the origin and genetics of human malaria virulence factors could aid in basic understanding of the causes of malaria and provide targets for drugs and vaccines. The study was published online on October 12, 2015 in an open-access article in Nature Communications. The article is titled “ "Ape Parasite Origins of Human Malaria Virulence Genes.” "The evolution of these key virulence determinants doesn't occur in the same way as in other pathogens. Instead of gradually changing by mutation, as the flu virus, these malaria parasites exchange intact gene segments, like shuffling a deck of cards," said Caroline Buckee, Ph.D., Assistant Professor of Epidemiology at Harvard’s Chan School and senior author of the study. Malaria kills more than 500,000 people a year, mostly children in Sub-Saharan Africa. Severe disease syndromes in human malaria--including severe malarial anemia, pregnancy-associated malaria, and cerebral malaria--have been linked with the malaria parasite's ability to cause infected red blood cells to bind to the inner lining of blood vessels. This ability of the infected cells to adhere in this way--which is key to malaria's virulence--is linked with certain genes called var genes.

October 11th

Boehringer Ingelheim’s Investigational Biologic Cleared Skin Better, Faster, and for Longer Than Ustekinumab in Phase II Psoriasis Study

New results from a Phase II head-to-head psoriasis study showed superior efficacy of Boehringer Ingelheim’s investigational biologic compound BI 655066, over ustekinumab, Boehrninger Ingelheim announced on October 8, 2015. After nine months, 69 percent of patients with moderate-to-severe plaque psoriasis maintained clear or almost clear skin (PASI 90) with BI 655066 in the higher dose group compared to 30 percent of patients on ustekinumab. Patients also achieved this skin clearance significantly faster (approximately eight weeks versus approximately 16 weeks) and for more than two months longer (≥ 32 weeks versus 24 weeks) than those on ustekinumab. In addition, completely clear skin (PASI 100) was maintained after nine months in nearly triple the percentage of patients on BI 655066 compared with ustekinumab (43 percent versus 15 percent). "These results are striking. They further strengthen our understanding of the potential skin improvement that can be achieved with BI 655066, in moderate-to-severe plaque psoriasis. We saw a third more patients achieve clearer skin in a short time period. And this clearance was maintained longer compared to the commonly used treatment ustekinumab," commented Kim A. Papp, M.D., Ph.D., President of Probity Medical Research, Waterloo, Ontario, Canada. "Achieving clear skin quickly and maintaining clearance is an important goal for patients who have to deal with the daily impact of psoriasis." These meaningful 24-week findings from a Phase II study in psoriasis were presented on October 8, 2015 in an oral presentation by Dr. Papp at the 24th European Academy of Dermatology and Venereology (EADV) Congress in Copenhagen, Denmark.

FDA Approves Merck’s Keytruda (Ab to PD-1) for Treatment of Advanced Non-Small-Cell Lung Cancer (85% of All Lung Cancer); Companion Test to ID Patients Most Likely to Benefit Also Approved

Pembrolizumab (trade name Keytruda), a drug that has already been proven to extend the lives of people with advanced melanoma, was approved on October 2, 2015 by the U.S. Food and Drug Administration (FDA) to treat advanced non-small-cell lung cancer (NSCLC) in patients whose tumors express the protein PD-L1 (programmed cell death ligand 1). Keytruda is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, which is the first test designed to detect PD-L1 expression in NSCLC. Keytruda is marketed by Merck & Co., based in Whitehouse Station, New Jersey, and the PD-L1 IHC 22C3 pharmDx diagnostic test is marketed by Dako North America Inc. in Carpinteria, California. Richard Pazdur, M.D., Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research said that the “approval of Keytruda gives physicians the ability to target specific patients who may be most likely to benefit from this drug.” The clinical trial study of Keytruda in advanced NSCLC represents the largest published research to date using immunotherapy to treat lung cancer, and the trial was conducted at UCLA and 29 other sites in the U.S., Europe, and Australia. “The approval of this drug and a test to identify patients most likely to benefit has the potential to transform the way that lung cancer is treated,” said Dr. Edward Garon, the study’s principal investigator and a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “The quality and duration of disease response that was seen in the trial had previously been extremely rare in lung cancer.

mRNAs Coded by Most Complicated Gene Known in Nature Are Sequenced Using Hand-Held MinION Nanopore Sequencer; Single Dsc1 Gene in Drosphila Can Potentially Code for Over 38,000 Protein Isoforms

University of Connecticut (UConn) researchers have sequenced cDNA from the mRNA coded for by the most complicated gene known in nature (Dsc1 which controls brain wiring in Drosophila), using a hand-held sequencer no bigger than a cell phone. Genomicists Brenton Graveley, Ph.D., from the UConn Institute of Systems Genomics, postdoctoral fellow Mohan Bolisetty, Ph.D., and graduate student Gopinath Rajadinakaran teamed up with UK-based Oxford Nanopore Technologies to show that that company's MinION nanopore sequencer can sequence genes faster, better, and at a much lower cost than the standard technology. They published their findings online on September 30, 2015 in an open-access article in Genome Biology. The article is titled “Determining Exon Connectivity in Complex mRNAs by Nanopore Sequencing.” The scientists believe their published results demonstrate that nanopore sequencing can be used to deconvolute individual isoforms and that it has the potential to be a powerful method for comprehensive transcriptome characterization. If your genome were a library and each gene was a book, some genes would be straightforward reads, but some would be more like a "Choose Your Own Adventure" novel. Researchers often want to know which version of the gene is actually expressed in the body, but for complicated, choose-your-own-adventure genes, that has been impossible. Dr. Graveley, Dr. Bolisetty, and Rajadinakaran solved the puzzle in two parts. The first was to find a better gene-sequencing technology. In order to sequence a gene using the old, existing technology, researchers typically first make many copies of it, using the same chemistry our bodies use.

October 10th

Recurrent Mutations in Epigenetic Modifiers and JAK-STAT Pathway Seen in Sezary Syndrome, a Rare, Aggressive Leukemia; Results Highlight Genetic Vulnerabilities That Can Be Targeted in Precision Medicine Therapies

Sezary syndrome (SS), an aggressive leukemia of mature T cells, is more complicated at a molecular level than ever suspected, according to investigators from the Perelman School of Medicine at the University of Pennsylvania, and from collaborating institutions. With a poor prognosis and limited options for targeted therapies, fighting SS needs new treatment approaches. The team's results uncover a previously unknown, complex genomic landscape of this cancer, which can be used to design new personalized drug regimens for SS patients based on their unique genetic makeups. SS is a rare condition. Its incidence is estimated to be about 0.3-2 cases per 100,000 in the United States each year, and those patients have a five-year survival rate of less than 30 percent. Penn Medicine has one of the largest referral clinics for treatment of SS patients in the country. Taking a thorough approach to find SS mutations, senior authors Megan S. Lim, M.D., Ph.D., a Professor of Pathology and Laboratory Medicine, and Kojo Elenitoba-Johnson, M.D., the Peter C. Nowell, M.D. Professor and Director of the Center for Personalized Diagnostics, were not disappointed. "We basically found chromosomal chaos in all of our samples," Dr. Elenitoba-Johnson said. The research results were published online on September 29, 2015 in an open-access article in Nature Communications. The title of the article is “Genomic Analyses Reveal Recurrent Mutations in Epigenetic Modifiers and the JAK–STAT Pathway in Sézary Syndrome.” The team integrated three complementary gene sequencing approaches to look for mutations in tumor cells from SS patients: whole-genome sequencing in six subjects, exome sequencing of all protein-coding regions in 66 subjects, and comparing variation in the number of copies of all genes across the genome in 80 subjects.

Protein Gates on Nanovesicles Designed to Open Only at Specific pH Values; Can Trigger Reaction and Release Active Agents at Desired Location

Researchers at the University of Basel in Switzerland have succeeded in building protein gates for artificial nanovesicles that open only under specific conditions. The gate responds to certain pH values, triggering a reaction and releasing active agents at the desired location. This is described in a study published online on October 2, 2015, in the journal Nano Letters. The article is titled “Stimuli-Triggered Activity of Nanoreactors by Biomimetic Engineering Polymer Membranes.” Tiny nanovesicles can protect active agents until they arrive in specific environments, such as at the target site in the body. In order to trigger a chemical reaction and release the contents at that location, the outer casing of the synthetically produced vesicles must become permeable at the correct point in time. Working under Professor Cornelia Palivan, researchers from the Swiss Nanoscience Institute have now developed a membrane gate that opens on demand. This means that the enzymes inside a nanocapsule become active under exactly the right conditions and act on the diseased tissue directly. The gate is made up of the chemically modified membrane protein OmpF, which responds to certain pH values. At neutral pH in the human body, the membrane is impermeable, but if it encounters a region with acidic pH, the protein gate opens and substances from the surrounding area can enter the nanocapsule. In the resulting enzymatic reaction, the capsule's contents act on the incoming substrate and the product of this reaction is released. This method could be applied, for example, to inflamed or cancerous tissue, which often exhibits a slightly acidic pH value.

Non-Heritable Parkinson’s Disease (90-95% of PD) May Be Caused by Functional Changes in Interferon-Beta; IFNβ Gene Therapy in Animal Model Prevents Neuronal Death & Disease Effects

An estimated seven to ten million people worldwide are living with Parkinson's disease (PD), which is an incurable and progressive disease of the nervous system affecting movement and cognitive function. More than half of PD patients develop progressive disease showing signs of dementia similar to Alzheimer's disease. A research team at University of Copenhagen, Denmark, has discovered that non-inheritable PD may be caused by functional changes in the immune regulating gene Interferon-beta (IFNβ) (image). Treatment with IFNβ-gene therapy successfully prevented neuronal death and disease effects in an experimental model of PD. The results were published in the October 8, 2015 issue of the prestigious journal Cell. The Cell article is titled “Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson’s Disease-Like Dementia.” The human brain consists of approximately 100 billion neurons, which coordinate activities in all parts of the body. At the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, the group of Professor Shohreh Issazadeh-Navikas has discovered that the immune gene IFNβ plays a vital role in keeping neurons healthy. “We found that IFNβ is essential for neurons ability to recycle waste proteins. Without this, the waste proteins accumulate in disease-associated structures called Lewy bodies and, with time, the neurons die, explains Assistant Professor Patrick Ejlerskov, the first author of this report. The research team found that mice missing IFNβ developed Lewy bodies in parts of the brain that control body movement and restoration of memory, and, as a result, they developed disease and clinical signs similar to those of patients with PD and dementia with Lewy bodies (DLB).

Diamonds Act As Beacons in MRI Scans; By Attaching Chemotherapeutic Targeted Cancer Agents to Hyper-Polarized Nano-Diamonds, Path of Agent Through Body Can Be Tracked

Physicists from the University of Sydney in Australia have devised a way to use diamonds to identify cancerous tumors before they become life threatening. Their findings, published online on October 9, 2015 in an open-access article in Nature Communications, reveal how a nanoscale, synthetic version of the precious gem can light up early-stage cancers in non-toxic, non-invasive Magnetic Resonance Imaging (MRI) scans. The article is titled “Hyperpolarized Nanodiamond with Long Spin Relaxation Times.” Targeting cancers with tailored chemicals is not new, but scientists struggle to detect where these chemicals go because, short of a biopsy, there are few ways to see if a treatment has been taken-up by a cancer. Led by Professor David Reilly from the School of Physics, researchers from the University of Sydney investigated how nanoscale diamonds could help identify cancers in their earliest stages. "We knew nano diamonds were of interest for delivering drugs during chemotherapy because they are largely non-toxic and non-reactive," says Professor Reilly. "We thought we could build on these non-toxic properties realizing that diamonds have magnetic characteristics enabling them to act as beacons in MRIs. We effectively turned a pharmaceutical problem into a physics problem." Professor Reilly's team turned its attention to hyperpolarizing nano-diamonds, a process of aligning atoms inside a diamond so they create a signal detectable by an MRI scanner. "By attaching hyperpolarized diamonds to molecules targeting cancers, the technique can allow tracking of the molecules' movement in the body," says Ewa Rej, Ph.D., the paper's lead author.

CHOP-Led Study More Precisely Calculates Heritability of Nine Autoimmune Diseases That Begin in Childhood; Highest Heritability Seen in Type 1 Diabetes & Juvenile Idiopathic Arthritis

Scientists have calculated more precise measurements of heritability--the influence of underlying genes--in nine autoimmune diseases that begin in childhood. The research may strengthen researchers' abilities to better predict a child's risk for associated autoimmune diseases. Autoimmune diseases, such as type 1 diabetes, Crohn's disease, and juvenile idiopathic arthritis, collectively affect 1 in 12 persons in the Western Hemisphere. These diseases represent a significant cause of chronic disability. "The results from this study enable us to better understand the genetic component of these diseases and how they are genetically related to each other, thereby explaining why different autoimmune disorders often run in the same family," said study leader, Hakon Hakonarson, M.D., Ph.D., Professor of Pediatrics and Director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP). The study was published online on October 9, 2015 in an open-access article in Nature Communications. Co-authors contributed gene data from more than 20 hospitals and research centers in the U.S. and overseas. The article is titled “Genetic Sharing and Heritability of Pediatric Age of Onset Autoimmune Diseases.” The research encompassed nine pediatric-onset autoimmune diseases (pAIDs): type 1 diabetes, celiac disease, juvenile idiopathic arthritis, common variable immunodeficiency, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, psoriasis, and ankylosing spondylitis. The study team compared genome-wide association study data from those diseases to data from pediatric-onset epilepsy, a non-autoimmune disease. In all, the study team analyzed data from over 5,000 unrelated pAID patients drawn from the CHOP pediatric network and from 36,000 healthy controls.