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Archive - Nov 12, 2015

Marshfield Clinic Data (37,000 Patients) Review Shows Those Receiving L-DOPA for Parkinson’s Demonstrate Resistance to Age-Related Macular Degeneration (AMD); Later Review of Data for 87 Million Patients Confirms This Finding

In what may prove to be a major scientific breakthrough, reviews of voluminous medical records data indicate that a drug (L-DOPA) used to treat Parkinson's and related diseases may be able to delay or prevent macular degeneration, the most common form of blindness among older Americans. The findings, published online on October 30, 2015 in an open-access article in the American Journal of Medicine (AJM), represent possibly ground-breaking progress in the fight against age-related macular degeneration (AMD), which affects as many as 11 million Americans. The title of the new AJM article is “Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration." AMD hinders central vision, and even when it does not lead to blindness, it can severely reduce the ability to read, drive, and recognize faces. In the new study, supported in part by the BrightFocus Foundation, researchers discovered a biological connection between more darkly pigmented eyes, which are known to be resistant to AMD, and increased levels of a chemical called L-DOPA in those eyes. Because L-DOPA is frequently prescribed for Parkinson's patients, the researchers wanted to know whether patients who received the drug L-DOPA as treatment for Parkinson's or other diseases were protected from AMD. By combing through massive databases of medical chart data, they reported that patients receiving L-DOPA were, in fact, significantly less likely to get AMD, and when they did, its onset was significantly delayed. "Rather than looking at what might cause AMD, we instead wondered why certain people are protected from AMD. This approach had never been [taken] before," says senior author Brian McKay, Ph.D., of the University of Arizona.

New Tool (iSRAP) Developed for Rapid Profiling of Small RNA-Seq Data

A new open-access article, published online today (November 12, 2015) in the Journal of Extracellular Vesicles (JEV), describes the development of a one-touch, integrated small RNA analysis pipeline (iSRAP) research tool that is composed of widely used tools for rapid profiling of small RNAs. The authors say that their performance test of the new iSRAP tool, using publicly and in-house available data sets, demosntrates its ability at comprehensive profiling of small RNAs of various classes, and at analysis of differentially expressed small RNAs. They further assert the the iSRAP tool offers comprehensive analysis of small RNA sequencing data that leverage informed decisions on the downstream analyses of small RNA studies, including those of extracellular vesicles (EVs) such as exosomes. In their article summary, the authors state the new iSRAP tool “provides a flexible and integrated environment for small RNA expression analysis using a single command. The flexible and powerful features of iSRAP enable a comprehensive analysis of small RNAs, which covers from quality assessment of input data to differential expression analysis and visualization of results with the ease of use. iSRAP can potentially serve as a platform for rapid analysis of transcriptomic data so that a better-informed decision can be made on the downstream analyses.” In the background for their report, the authors note that “small non-coding RNAs have been significantly recognized as the key modulators in many biological processes, and are emerging as promising biomarkers for several diseases.” They say that “these RNA species are transcribed in cells and can be packaged in extracellular vesicles, which are small vesicles released from many biotypes, and are involved in intercellular communication.”

TGen Shows That Small-Molecule TROY-Inhibitor PPF May Work As Adjuvant, Together with Standard-of-Care TMZ & Radiation, to Limit Glioblastoma Invasion and Improve Clinical Outcome for GBM Patients

In what may be a significant breakthrough, the Translational Genomics Research Institute (TGen) in Phoenix, Arizona has identified a drug, propentofylline (PPF), that could help treat patients with deadly brain cancer. In a study published online on November 12, 2015 in the Journal of NeuroOncology, TGen researchers report that PPF works to limit the spread of glioblastoma multiforme (GBM), the most common primary tumor of the brain and central nervous system, by targeting a protein called TROY. In addition, TGen laboratory research also found that PPF increases the effectiveness of a a current standard-of-care chemotherapy drug called temozolomide (TMZ), and radiation, to treat glioblastoma. "We showed that PPF decreased glioblastoma cell expression of TROY, inhibited glioma cell invasion, and made brain cancer cells more vulnerable to TMZ and radiation," said Dr. Nhan Tran, Associate Professor and Head of TGen's Central Nervous System Tumor Research Lab. An advantage of small-molecule PPF, which has previously been used in clinical trials in an attempt to treat Alzheimer's disease and dementia, is that it can penetrate the blood-brain barrier and reach the tumor. And, the FDA has already approved it. The Journal of Neuro-Oncology article is titled “Propentofylline Inhibits Glioblastoma Cell Invasion and Survival by Targeting the TROY Signaling Pathway.” "Our data suggests that PPF, working in combination with TMZ and radiation, could limit glioblastoma invasion and improve the clinical outcome for brain tumor patients," said Dr. Tran, the study's senior author. This study was funded, in part, by The Ben & Catherine Ivy Foundation.

Single-Molecule, Real-Time (SMRT) Sequencing Using PacBio RS II Sequencing System Enables Genome Sequencing of Drought-Tolerant “Resurrection Plant” The Effort Is Part of PacBio’s “Most Interesting Genome in the World" Grant Program

A new paper published online on November 11, 2015 in an open-access article in Nature reports the virtually complete draft genome sequence of Oropetium thomaeum, a grass species that can re-grow after exposed to extreme drought when water again becomes available. The plant's 245-Mb genome was analyzed with 72X coverage on the PacBio® RS II Sequencing System by researchers at the Donald Danforth Plant Science Center (DDPSC) in St. Louis, Missouri. The resulting assembly has an accuracy of 99.99995% and includes telomere and centromere sequences, long terminal repeat retrotransposons, tandem duplicated genes, and other difficult-to-assemble genomic elements. This plant was sequenced through the Pacific Biosciences "Most Interesting Genome in the World" grant program designed to help scientists determine the biological mechanisms behind its extreme drought tolerance for potential application in crop improvement. The Nature article is titled “Single-Molecule Sequencing of the Desiccation Tolerant Grass Oropetium thomaeum.” The senior author of the Nature article is is Todd Mockler, Ph.D., Associate Member, DDPSC, Geraldine and Robert Virgil Distinguished Investigator, DDPSC; and the lead authors are Post-Doctoral Associate Robert VanBuren, Ph.D., DDPSC; and Doug Bryant, Ph.D., DDPSC. Scientists from numerous other institutions (see below) also contributed to this effort. "We submitted the idea to sequence the resurrection grass Oropetium thomaeum to PacBio because it has the smallest known genome among the grasses. Having the genomic data of a highly drought-tolerant species is really powerful in facilitating crop improvement, and providing a valuable resource for the plant comparative genomics community.

Longer Reproductive Period, Contraceptive Use, IUD Use All Associated with Better Cognitive Function in Elderly Women; Shorter Reproductive Period, More Full-Term Pregnancies, & No Incomplete Pregnancies All Linked to Worse Cognitive Function

Researchers led by Professor Jun-Fen Lin at the Zhejiang Provincial Center for Disease Control and Prevention in China have found that reproductive history, an important modifier of estrogen exposure across women's lifetimes, is associated with risk of cognitive impairment in post-menopausal women. These findings are published online on September 28, 2015 in the Journal of Alzheimer's Disease. In particular, the scientists found a longer reproductive period (menarche to menopause) was associated with significantly better cognitive function in elderly women. On the other hand, shorter reproductive period, higher number of full-term pregnancies, and no incomplete pregnancies are all significantly associated with increased risk of cognitive impairment. Further, the use of contraceptives and/or IUDs was associated with decreased risk of cognitive impairment. The article is titled “Reproductive History and Risk of Cognitive Impairment in Elderly Women: A Cross-Sectional Study in Eastern China.” Professor Lin notes that post-menopausal women carry an increased risk of developing Alzheimer's disease (AD) than age-matched men, probably due to the marked reduction of estrogen level that occurs following menopause. Animal and in vitro studies have identified that estrogen has several possible neuroprotective effects on cognitive function. There has been substantial research on the association between reproductive history, as an important modifer of estrogen exposure, and risk of cognitive impairment. However, there are still inconsistencies in some epidemiological and clinical studies. Only a few studies have been conducted in Chinese populations. The Zhejiang Major Public Health Surveillance Program (ZPHS) is a community-based cohort study focusing on aging and health among elderly in Zhejiang, China.

Mayo Clinic Researchers ID Completely Novel Mechanism for Predisposition to Type 2 Diabetes; Understanding Glucagon-Suppressing Effect of TCF7L2 Gene Variant May Lead to Novel Therapies

Researchers at the Mayo Clinic in Rochester, Minnesota, together with colleagues from the Universita’ di Padova in Italy, have discovered an unexpected effect from a gene already known to increase diabetes risk. The scientists had assumed that the specific allele in the gene TCF7L2 that increases the risk of type 2 diabetes, impairs insulin production in response to increased insulin resistance. Some slight evidence of that was found in the current Mayo Clinic study, but more significantly, the researchers discovered that this variant impaired a person’s ability to balance blood sugar (glucose) by suppressing glucagon – the hormone that raises the level of glucose in the bloodstream. The findings were published online on November 2, 2015, in the journal Diabetes. The article is titled “TCF7L2 Genotype and α-Cell Function in Nondiabetic Humans.” “This was surprising. It demonstrates a completely novel mechanism of predisposition to diabetes that could lead to novel therapies,” says Adrian Vella, M.D., Mayo Clinic endocrinologist and senior author of the study. “Ultimately, this sheds new light on how this gene actually predisposes to diabetes.” Dr. Vella notes that more-detailed clinical studies need to be done to confirm the finding, as well as to better understand how this affects diabetes in more heterogeneous populations over the long term.

[Mayo Clinic press release] [Diabetes abstract]

Exosome-Based Approach to Diagnose Lupus in Patients with Renal Impairment; High Levels of miRNA-146a in Urine-Derived Exosomes from Patients May Be Diagnostic for This Pathology

Researchers at the INCLIVA Biomedical Research Institute in Valencia, Spain, together with collaborators, have demonstrated the presence of extracellular vesicles (EVs) in the urine of patients diagnosed with lupus and renal impairment (lupus nephritis) and shown that exosomes (a subset of EVs) in this urine contain unusually high levels of microRNA-146a (miR-146a) that may be diagnostic for this pathology. The work was originally published online on September 21, 2015 in the open-access journal PLOS ONE. This article was titled “Increased Urinary Exosomal MicroRNAs in Patients with Systemic Lupus Erythematosus." A related review article titled “Extracellular Vesicles as Biomarkers of Systemic Lupus Erythematosus,” was published online at about the same time in the open-access journal Disease Markers. Lupus (systemic lupus erythematosus or SLE) is a chronic autoimmune disease that can affect almost every organ of the body, joints, kidneys, heart, skin, blood vessels, lungs, etc., whose cause is unknown. It is a very heterogeneous disease, with symptoms that come and go in outbreaks, hence the complexity of diagnosis. To date, lupus has no single diagnostic technique that has become final. The diagnosis is mainly based on symptoms, clinical findings, and complementary laboratory tests. It is a disease that most often affects women, at a time of life in which they are fertile, between 20 and 40 years. According to the Spanish Society of Rheumatology, lupus currently affects about 40,000 people in Spain. Coordinated by the Scientific Director of the INCLIVA Research Institute, Josep Redon, M.D., Ph.D., the project has focused on lupus patients with renal impairment (lupus nephritis), as, in the kidney, microRNAs play an indispensable role in regulating the mechanisms of development and maintenance renal function.

Chimpanzees Separated from Mothers in First Two Years of Life Show Impaired Social Behavior As Adults; Separated Chimps Who Have Since Lived in Social Groups for 40 Years Still Show Impaired Behavior

Wild-caught chimpanzees, who were orphaned and imported from Africa in their early infancy, exhibit impaired social behavior, even as adults, and even when living in social groups for many years. So far, long-term effects of early traumatic experiences on social behavior were known only for humans and socially isolated chimpanzees. An Austrian-Dutch research team, led by Elfriede Kalcher-Sommersguter, Ph.D., of the University of Graz and Jorg Massen. Ph.D., of both the University of Vienna and Utrecht University, published these results online on November 10, 2015 in Scientific Reports. The article is titled “Early Maternal Loss Affects Social Integration of Chimpanzees Throughout Their Lifetime.” Between 1950 and 1980, thousands of chimpanzee infants were wild-caught in West Africa and exported to Europe, Japan, and the USA, where these chimpanzees have been used in biomedical research. But also many zoos have wild-caught chimpanzees: the so-called founder populations. The new study shows that chimpanzees, who were maternally deprived within their first two years of life, were restricted in their social grooming behavior, even decades later. Social grooming is highly important for the establishment and maintenance of social relationships within groups of chimpanzees. "The orphaned chimpanzees had a lower number of partners they groomed and were less active than were chimpanzees reared by their mothers," says Dr. Kalcher-Sommersguter. These deficits in social grooming are found, not only in chimpanzees that were kept singly caged for decades in a biomedical laboratory, before being re-socialized, but also in individuals, who, after being orphaned, grew up in social groups in a zoo.