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Archive - Oct 10, 2015

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.

Fungus-Farming Leaf-Cutter Ants May Be Controlled by Escovopsis Parasitic Fungus That Destroys the Ants’ Larval Food Source: Their Farmed Mutualistic Fungus

A 15-year study of leaf-cutter ants and their relatives across North and South America has found that their nests are susceptible to infection by a diverse group of specialized fungal parasites. The discovery, by biologists from Rice University, São Paulo State University in Rio Claro, Brazil, and the University of Texas at Austin (UT-Austin), could provide new clues for controlling the agricultural and garden pests. The study, which was published online on September 30, 2015 in the open –access journal Royal Society Open Science, is one of the largest ever undertaken of parasites associated with leaf-cutter ants. The study began in 2000 and involved collecting, cataloging, and analyzing samples of parasitic fungi called Escovopsis from dozens of colonies of leaf-cutter ants and their relatives in Brazil, Argentina, Panama, Mexico, and the Caribbean islands of Guadeloupe and Trinidad and Tobago. Researchers identified 61 new strains of the fungi, which attack the ants' food source. The article is titled “Shared Escovopsis Parasites Between Leaf-Cutting and Non-Leaf-Cutting Ants in the Higher Attine Fungus-Growing Ant Symbiosis.” According to Wikipedia, different species of leaf-cutter ants farm different species of fungus as mutualistic partners, but all of the fungi the ants use are members of the Lepiotaceae family. The ants actively cultivate their fungus, feeding it with freshly cut plant material and keeping it free from pests and molds. This mutualistic relationship is further augmented by another symbiotic partner, a bacterium that grows on the ants and secretes chemicals; essentially, the ants use portable antimicrobials. Leaf-cutter ants are sensitive enough to adapt to the fungi's reaction to different plant material, apparently detecting chemical signals from the fungus.

Type 2 Diabetes Risk and Body Shape in Women Are Influenced by Genetic Variant Near KLF14 Gene; KLF14 Gene Expression Regulates Hundreds of Genes Governing How and Where Fat Is Stored in Women’s Bodies; Findings Reported at ASHG 2015 Annual Meeting

A genetic variant near the KLF14 gene regulates hundreds of genes that govern how and where women’s bodies store fat, which affects their risk of developing Type 2 diabetes, according to research presented on Saturday, October 10, at the American Society of Human Genetics (ASHG) 2015 Annual Meeting in Baltimore, Maryland. Specifically, different alleles, or versions, of the variant cause fat-storing cells to function differently. “At the whole-body level, these differences between alleles are not associated with changes to overall weight or body mass index, but they do affect women’s hip circumference,” explained Kerrin Small, Ph.D., Head of the Genomics of Regulatory Variation Research Group at King’s College London and lead author on the study. “Previous studies have shown that, on average, women who carry fat in their hips – those with a ‘pear-shaped’ body type – are significantly less likely to develop diabetes than those with smaller hips. Looking at the variant we studied, large-scale genome-wide association studies show that women with one allele tend to have larger hips than women with the other one, which would have a protective effect against diabetes,” she said. The variant is located near the KLF14 gene, which encodes a protein that Dr. Small and her colleagues discovered directly regulates the expression of hundreds of other genes in fat tissue. KLF14 is maternally imprinted, which means that a person’s expression of KLF14 and the resulting effects on fat tissue are determined by the version of the gene inherited from his or her mother; the father’s allele does not affect levels of this regulatory protein. Researchers first identified the relationship between the variant near KLF14 and Type 2 diabetes risk in a large, genome-wide association study of a broad population.

Key Target of Aspirin’s Active Metabolite Salicylic Acid Identified; SA Blocks Activity of HMGB1 Protein, a Very General Inflammation Trigger; Much More Potent SA Derivatives Synthesized & Also Isolated from Licorice Plant

Researchers have found that salicylic acid (main breakdown product of aspirin) targets the activities of HMGB1 (high mobility group box 1) (image), an inflammatory protein associated with a wide variety of diseases, offering hope that more powerful aspirin-like drugs may be developed. Aspirin is one of the oldest and most commonly used medicines, but many of its beneficial health effects have been hard for scientists and physicians to explain. A recent study conducted by researchers at the Boyce Thompson Institute (BTI) in Ithac, New York, in collaboration with colleagues at Rutgers University in New Jersey and at San Raffaele University and Research Institute in Italy, shows that aspirin's main breakdown product, salicylic acid, blocks HMGB1, which may explain many of the drug's therapeutic properties. The findings were published on September 23, 2015 in an open-access article in the journal Molecular Medicine. The article is titled “Aspirin′s Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses.” "We've identified what we believe is a key target of aspirin's active form in the body, salicylic acid, which is responsible for some of the many therapeutic effects that aspirin has. This protein, HMGB1, is associated with many prevalent, devastating diseases in humans, including rheumatoid arthritis, heart disease, sepsis, and inflammation-associated cancers, such as colorectal cancer and mesothelioma," said senior author Daniel Klessig, Ph.D., a Professor at BTI and Cornell University. Aspirin's pain relieving effects have long been attributed to its ability to block the enzymes cyclooxygenase 1 and 2, which produce prostaglandins--hormone-like compounds that cause inflammation and pain--a discovery that netted its discoverer, Dr. John Vane, a Nobel prize.

Antioxidants Can Double Rate of Melanoma Metastasis; New Results Reinforce Earlier Findings That Antioxidants Hasten Progression of Lung Cancer; Researchers Advise Cancer Patients to Avoid Antioxidant Supplements

Fresh research at Sahlgrenska Academy, University of Gothenburg, Sweden, has found that antioxidants can double the rate of melanoma metastasis in mice. The results reinforce previous findings that antioxidants hasten the progression of lung cancer. According to Professor Martin Bergö of the Academy, people with cancer or an elevated risk of developing the disease should avoid nutritional supplements that contain antioxidants. Researchers at Sahlgrenska Academy demonstrated in January 2014 that antioxidants hastened and aggravated the progression of lung cancer. Mice that were given antioxidants developed additional and more aggressive tumors. Experiments on human lung cancer cells confirmed the results. Given well-established evidence that free radicals can cause cancer, the research community had simply assumed that antioxidants, which destroy them, provide protection against the disease. Found in many nutritional supplements, antioxidants are widely marketed as a means of preventing cancer. Because the lung cancer studies called the collective wisdom into question, they attracted a great deal of attention. The follow-up studies at Sahlgrenska Academy have now found that antioxidants double the rate of metastasis in malignant melanoma, the most perilous type of skin cancer. The new results were published online on October 7, 2015 in Science Translational Medicine. The article is titled “Antioxidants Can Increase Melanoma Metastasis in Mice.” "As opposed to the lung cancer studies, the primary melanoma tumor was not affected," Professor Bergö says. "But the antioxidant boosted the ability of the tumor cells to metastasize, an even more serious problem because metastasis is the cause of death in the case of melanoma.

Hard-to-Detect Balanced Chromosomal Abnormalities (BCAs) May Cause Large Percentage of Neurodevelopmental Birth Defects; Findings from New MGH/Broad Institute Study Reported at ASHG 2015 Annual Meeting

Balanced chromosomal abnormalities (BCAs), a category of structural changes to the human genome, may account for a large portion of birth defects related to brain development and function, according to research presented on Saturday, October 10, at the American Society of Human Genetics (ASHG) 2015 Annual Meeting in Baltimore, Maryland. BCAs are changes to the structure of an individual’s chromosomes, in which one or more fragments of DNA breaks apart from the regions around it and is reattached elsewhere in the genome, either on the same chromosome or on a different one. In their simplest form, a single fragment is moved to another region of the genome, but more complex BCAs may involve more than one fragment from more than one chromosome. Unlike chromosomal deletions or duplications, BCAs do not result in the gain or loss of any genetic material. However, they do disrupt the function of DNA at the breakpoints of the fragments involved, in both their original locations and their new ones, and BCAs have been implicated in neurodevelopmental birth defects. “We studied BCAs in 111 patients with congenital neurodevelopmental conditions and 36 with other conditions and mapped where the breakpoints were,” explained Claire Redin (photo), Ph.D., a postdoctoral researcher at Massachusetts General Hospital (MGH) and the Broad Institute, and first author on the new study. “By mapping the breakpoints, we were able to identify genes that were disrupted in patients with birth defects, which suggests that these genes play a key role in normal brain development,” she said. Because no genetic material is gained or lost, conventional tools for genome analysis cannot generally detect BCAs. Thus, they have not received much attention as a significant cause of disease. To overcome this challenge, Dr.