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Archive - Jun 2019

Date

June 2nd

Atlas of ~10,000 Genome Regions of Epigenetic Variation Between Individuals, But Consistent Across Different Tissues in Individuals, Established for DNA Methylation Marks Detectable in Blood; Work Should Aid Unraveling of Epigenetic Causes of Disease

More than 15 years after scientists first mapped the human genome, most diseases still cannot be predicted based on one's genes, leading researchers to explore epigenetic causes of disease. But the study of epigenetics cannot be approached in the same way as genetics, so progress has been slow. Now, researchers at the USDA/ARS Children's Nutrition Research Center at Baylor College of Medicine and Texas Children's Hospital have determined a unique fraction of the genome that scientists should focus on. Their report, which provides a "treasure map" to accelerate research in epigenetics and human disease, was published online on June 3, 2019 in Genome Biology. The open-access article is titled “A Genomic Atlas of Systemic Interindividual Epigenetic Variation in Humans.” Epigenetics is a system for molecular marking of DNA that tells the different cells in the body which genes to turn on or off in that cell type. But the cell-specific nature of epigenetics makes it challenging to study. Whereas a blood sample can be used to “genotype” an individual, most epigenetic marks in blood DNA provide no clues about epigenetic dysregulation in other parts of the body, such as the brain or heart. The authors note the following. “DNA methylation is thought to be an important determinant of human phenotypic variation, but its inherent cell type specificity has impeded progress on this question. At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample. We describe an unbiased screen for human genomic regions at which interindividual variation in DNA methylation is not tissue-specific.” Senior author Robert A.

June 1st

Novartis Drug Ribociclib (Kisqali®) Shows Significant Promise in Targeted Treatment of Young Women with Advanced HR+/HER2-Negative Breast Cancer, Who Are Also Treated with Standard-of-Care Endocrine Therapy, According to Announcement at ASCO 2019

On June 1, 2019, it was announced that the international, randomized phase III MONALEESA-7 clinical trial has found that adding the Novartis drug ribociclib (Kisqali®) to standard-of-care endocrine therapy significantly improved overall survival for pre-menopausal women with advanced hormone receptor (HR)-positive/HER2-negative breast cancer compared with endocrine therapy alone. After 42 months of follow-up, the survival rate was 70% for women who took the combination therapy compared with 46% for women who received endocrine therapy only. Advanced breast cancer is the leading cause of cancer death in women 20 to 59 years of age. The MONALEESA-7 study results were presented on June 1, 2019 at the American Society of Clinical Oncology (ASCO) Annual Meeting (https://meetings.asco.org/am/learn-engage )in Chicago, Illinois, and were featured in a June 1 ASCO press briefing. The ASCO abstract (LBA 1008) is titled “Phase III MONALEESA-7 trial of Premenopausal Patients with HR+/HER2- Advanced Breast Cancer (ABC) Treated with Endocrine Therapy ± Ribociclib: Overall Survival (OS) Results.” “This is the first study to show improved survival for any targeted therapy when used with endocrine therapy as a first-line treatment for advanced breast cancer,” said the study’s lead author Sara A. Hurvitz (photo), MD, Director of the Breast Cancer Clinical Research Program at the UCLA Jonsson Comprehensive Cancer Center in Los Angeles, CA. “The use of ribociclib as a front-line therapy significantly prolonged overall survival, which is good news for women with this terrible disease. Overall survival benefit is considered the 'gold standard' in cancer trials, but is challenging to achieve in HR+/HER2- metastatic breast cancer. MONALEESA-7 reached this important endpoint earlier than anticipated.

June 1st

Co-Expression Extrapolation (COXEN) Gene Analysis May Enable Prediction of Patient Response to Pre-Surgical Chemotherapy for Bladder Cancer

Data from a University of Colorado (CU) Cancer Center-led clinical trial show that a predictive tool called COXEN may show which bladder cancer patients will respond to pre-surgical chemotherapy, a step towards allowing doctors to offer such chemotherapy to patients likely to respond, while moving more efficiently to other treatment options with patients unlikely to benefit. Results of this trial will be presented Monday, June 3, at 8:00 am as an oral abstract at the 2019 American Society for Clinical Oncology (ASCO) Annual Meeting (ASCO abstract #4506) (http://abstracts.asco.org/239/AbstView_239_260635.html) in Chicago, Illinois. The title of the abstract is “A Randomized Phase II Study of Co-Expression Extrapolation (COXEN) with Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer.” "The idea is that for any individual tumor, its gene expression could tell us whether the cancer will respond to a certain kind of chemotherapy," says Thomas Flaig (photo), MD, Associate Dean for Clinical Research at CU School of Medicine, Chief Clinical Research Officer of UCHealth, and national principal investigator of the COXEN phase II clinical trial. "This is an important clinical application of a concept developed by investigators based in Colorado, which may have implications in predicting the response to chemotherapies across many cancer types." COXEN, which stands for “co-expression extrapolatiom,” was pioneered by former CU Cancer Center Director, Dan Theodorescu, MD, PhD, now Director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai in Los Angeles. Dr. Thoedorescu's lab used 60 human-derived cancer cell lines curated by the National Cancer Institute to develop a gene expression approach to predicting the sensitivity of these cells to various chemotherapies.

Gypsy Moth Has Largest Moth/Butterfly Genome Ever Sequenced; Analysis May Reveal Secrets of Extraordinary Resistance of Gypsy Moth Cells to Arboviruses Infection & Aid in Efforts to Combat Arboviruses Like Zika That Infect Humans

The European gypsy moth (EGM) is perhaps the country's most famous invasive insect, a nonnative species accidentally introduced to North America in the 1860s when a few escaped from a breeding experiment in suburban Boston. The caterpillars have been slowly eating their way across the continent ever since, causing widespread defoliation. In research that could lead to better bioinsecticides to protect forests and orchards, Drs. Don Gammon and Nick Grishin of the University of Texas (UT) Southwestern have sequenced the genomes of the EGM and its even more destructive cousin, the Asian gypsy moth (AGM). Their work, published in the January 29, 2019 issue of PNAS, reveals that the gypsy moth has the largest moth or butterfly genome (number of DNA base pairs) ever sequenced. The PNAS article is titled “Gypsy Moth Genome Provides Insights into Flight Capability and Virus–Host Interactions.” "The European gypsy moth has spread as far west as Minnesota and as far south as North Carolina. The rather slow spread (about 13 miles a year) is partly due to the fact that EGM females are flightless and must walk or be blown by the wind to disperse," said Dr. Gammon, Assistant Professor of Microbiology and a W.W. Caruth, Jr. Scholar in Biomedical Research at UT Southwestern. "In contrast, females of the Asian gypsy moth subspecies, which inhabits Asia and eastern Russia, have larger, more developed wings, and can fly." If the Asian gypsy moth were to become established in the United States, it would pose an even greater economic threat due to its ability to spread more swiftly, Dr. Gammon added. To guard against that possibility, the US Department of Agriculture has surveillance programs at several ports and regularly sprays virus-based bioinsecticides in endangered forests to kill gypsy moth caterpillars.

Non-Invasive Test for Heart Blood Flow Developed; CO2/O2-Based Cardiac Functional MRI Provides “Totally Novel Way of Doing Cardiac Stress Testing to Identify Patients with Ischemic Heart Disease, Eliminates Existing Risks & Can Be Used on All Patients”

An international team led by scientists from Lawson Health Research Institute (Canada) and Cedars-Sinai Medical Center (USA) is the first to show that magnetic resonance imaging (MRI) can be used to measure how the heart uses oxygen for both healthy patients and those with heart disease. Reduced blood flow to the heart muscle is the leading cause of death in the Western world. Currently, the diagnostic tests available to measure blood flow to the heart require injection of radioactive chemicals or contrast agents that change the MRI signal and detect the presence of disease. There are small but finite associated risks and it is not recommended for a variety of patients including those with poor kidney function. More than 500,000 tests are performed each year in Canada. "This new method, cardiac functional MRI (cfMRI), does not require needles or chemicals being injected into the body," says Dr. Frank Prato, Lawson’s Assistant Director for Imaging. "It eliminates the existing risks and can be used on all patients." The results of the new study, titled "Accurate Needle-Free Assessment of Myocardial Oxygenation for Ischemic Heart Disease in Canines Using Magnetic Resonance Imaging" was published online on May 29, 2019 in Science Translational Medicine. The research team included researchers from Lawson; Cedars-Sinai Medical Center, and University of California (USA); King's College (UK); University Health Network (Canada) and the University of Toronto (Canada); Siemens Healthineers (Germany); and the University of Edinburgh (UK). "Our discovery shows that we can use MRI to study heart muscle activity," explains Dr. Prato. "We've been successful in using a pre-clinical model and now we are preparing to show this can be used to accurately detect heart disease in patients."

Exosomes from Transplanted Stem Cells Aid Recovery from Heart Attack in Animal Model; Analysis (Liquid Biopsy) of Circulating Exosomes from Transplanted Cells Can Allow Scientists/Physicians to Understand the Mechanism & Extent of Recovery

Stem-cell based therapies to strengthen the heart muscle and treat other diseases are beginning to show promise in human clinical trials. However, other than observing clinical outcomes, lack of a repeatable, time-sensitive, and noninvasive tool to assess the effectiveness of the transplanted cells within the target organ has slowed progress in the stem cell field. Researchers from the University of Maryland School of Medicine (UMSOM), the University of Pennsylvania, and Emory University theorized that a blood test could be used to track the efficacy of transplanted stem cells. They aimed to achieve their goal by analyzing tiny cellular components called exosomes, secreted from the transplanted stem cells into the recipient blood. The researchers tested their theory in rodent models of heart attack, or myocardial infarction, after transplanting two types of human cardiac stem cells and monitoring their circulating exosomes. The researchers found that circulating exosomes delivered cell components to the target heart muscle cells, resulting in cardiac repair. The results of their work were published online on May 22, 2019 in Science Translational Medicine. The article is titled “Circulating Exosomes Derived from Transplanted Progenitor Cells Aid the Functional Recovery of Ischemic Myocardium.”“Exosomes contain the signals of the cells they’re derived from – proteins, as well as nucleic acids and micro ribonucleic acids (miRNAs) – which affect receptor cells and remodel or regenerate the organ we’re targeting,” said study co-senior author Sunjay Kaushal, PhD, MD, Professor of Surgery at UMSOM and Director of Pediatric Cardiac Surgery at the University of Maryland Children’s Hospital.