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Archive - Mar 2017

March 31st

Removal of Inhibitory Antibodies As New Treatment for Bronchiectasis with Antibiotic-Resistant Pseudomonas auruginosa

A study, published in the April 2017 issue of the American Journal of Respiratory and Critical Care Medicine, describes a new treatment pathway for antibiotic-resistant bacteria and infectious diseases with benefits for patients and health care providers. Researchers from the University of Birmingham and Newcastle University in the UK found that the unusual approach of removing antibodies from the blood stream reduced the effects of chronic infections, the requirement for days spent in hospital, and the use of antibiotics. In this study, the team identified two patients with bronchiectasis who suffered with chronic Pseudomonas aeruginosa infections that were resistant to many antibiotics: a 64-year-old male, diagnosed with bronchiectasis at age 15, and a 69-year-old female who had bronchiectasis from childhood. Bronchiectasis is a disease that leads to permanent enlargement of the airways in the lung and affects over 300,000 patients in the UK. Symptoms are debilitating for patients, and typically include a chronic cough, shortness of breath, coughing up blood, and chest pain. Bronchiectasis often affects patients beyond the age at which lung transplantation is possible. Chronic Pseudomonas aeruginosa lung infections commonly occur in patients suffering from bronchiectasis. Pseudomonas aeruginosa is a common bacterium that can cause disease and is known as a multidrug resistant pathogen, recognized for its advanced antibiotic resistance mechanisms and association with serious illnesses. The patients volunteered to be part of an explorative treatment that built on previous findings from the research group that were reported in 2014 (http://www.birmingham.ac.uk/news/latest/2014/08/11-Aug-14-Breakthrough-c...).

Experimental Small Molecule Shows Potential for Preventing Methamphetamine Relapse

FNew research from The Scripps Research Institute (TSRI) suggests that the reason methamphetamine (meth) users find it so hard to quit—88 percent of them relapse, even after rehab—is that meth takes advantage of the brain’s natural learning process. The TSRI study in rodent models shows that ceasing meth use prompts new neurons to form in a brain region tied to learning and memory, suggesting that the brain is strengthening memories tied to drug-seeking behavior. “New neuronal growth is normally thought of as a good thing, but we captured these new neurons assisting with ‘bad’ behaviors,” said Chitra Mandyam (photo), Ph.D., who led the research as an Associate Professor at TSRI before starting a new position at the Veterans Medical Research Foundation and the University of California, San Diego. The scientists discovered that they could block relapse by giving animals a synthetic small molecule to stop new neurons from forming. This molecule, called isoxazole-9 (Isx-9), also appeared to reverse abnormal neuronal growth that developed during meth use. The new research was published online on March 28, 2017 in Molecular Psychiatry. The article is titled “A Synthetic Small-Molecule Isoxazole-9 Protects Against Methamphetamine Relapse.” Neurons are born all the time in a process called neurogenesis. In a 2010 study, Dr. Mandyam and her colleagues at TSRI showed that increased neurogenesis is tied to a higher risk of drug relapse, but they weren’t sure of the new neurons’ role in the process. The researchers were especially curious about a “burst” of neurogenesis that occurs during abstinence from meth. The new study may explain why the brain is so eager to make neurons during abstinence: meth hijacks the natural neurogenesis process.

Circulating Adipose-Derived Exosomal miRNAs Can Regulate Gene Expression in Distant Tissues; Constitutes Newly Described Mechanism of Cell-Cell Crosstalk

Researchers from the Harvard Medical School, the Joslin Diabetes Center, and collaborating institutions have shown that adipose tissue is an important source of circulating exosomal miRNA in both mice and humans, and that different adipose depots contribute different exosomal miRNAs to the circulation. In an article published in the February 23, 2017 issue of Nature, the research team stated that its data shows that these adipose-derived circulating miRNAs can have far-reaching systemic effects, including on the regulation of mRNA expression and translation. The scientists note that adipose tissue transplantation, especially brown adipose tissue (BAT) transplantation, improves glucose tolerance and lowers levels of circulating insulin and FGF21, as well as of hepatic Fgf21 mRNA in recipient mice. Because the adipose-derived miRNAs are produced by different adipose depots, the levels of these miRNAs could also change in diseases with altered fat mass, such as lipodystrophy and obesity, or with altered adipose distribution and function, such as diabetes and aging. The researchers conclude that adipose derived exosomal miRNAs constitute a previously undescribed class of adipokines that can act as regulators of metabolism in distant tissues, providing a new mechanism of cell-cell crosstalk. The Nature article is titled “Adipose-Derived Circulating miRNAs Regulate Gene Expression in Other Tissues.” In addition to the Harvard Medical School and the Joslin Diabetes Center, the collaborating researchers came from Boston University, University Hospital in Zurich, Switzerland, Massachusetts General Hospital, and NIH.

[Nature abstract]

Three Additional Gene Loci Associated with Corneal Disease FECD

Corneal diseases are among the most common causes of visual impairment and blindness, with Fuchs endothelial corneal dystrophy (FECD), a gradual swelling and clouding of the cornea, being the most common reason for eventual corneal transplants. In work reported online on March 30,2017 in Nature Communications, researchers at the University of California San Diego School of Medicine, with colleagues at Case Western University, Duke University, the National Institutes of Health and elsewhere, have identified three novel genomic loci linked to FECD, which often clusters in families and is roughly 39 percent heritable. The open-acccess article is titled “Genome-Wide Association Study Identifies Three Novel Loci in Fuchs Endothelial Corneal Dystrophy.” “Previously, there was one known FECD locus. We've expanded that number to four," said the study's first author Natalie A. Afshari, M.D., Professor of Ophthalmology, Stuart Brown M.D. Chair in Ophthalmology in Memory of Donald Shiley, and Chief of Cornea and Refractive Surgery at the Shiley Eye Institute at UC San Diego Health. "These findings provide a deeper understanding of the pathology of FECD, which in turn will help us develop better therapies for treating or preventing this disabling disease." FECD affects the innermost layer of cells in the cornea (the transparent front cover of the eye), called the endothelium. The endothelium is responsible for maintaining the proper amount of fluid in the cornea, keeping it clear. FECD is a progressive disorder in which the endothelium slowly degrades, with lost clarity, pain, and severely impaired vision. It affects 4 percent of the U.S. population above age 40 and worsens with age. Women are two to four times more frequently affected than men.

March 30th

MIT Researchers Program RNA Vaccine That Could Protect Against Zika Virus

Using a new strategy that can rapidly generate customized RNA vaccines, MIT researchers have devised a new vaccine candidate for the Zika virus. The vaccine consists of strands of messenger RNA that are packaged into a nanoparticle that delivers the RNA into cells. Once inside cells, the RNA is translated into proteins that provoke an immune response from the host, but the RNA does not integrate itself into the host genome, making it potentially safer than a DNA vaccine or vaccinating with the virus itself. “It functions almost like a synthetic virus, except it’s not pathogenic and it doesn’t spread,” says Dr. Omar Khan, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and an author of the new study. “We can control how long it’s expressed, and it is RNA so it will never integrate into the host genome.” This research also yielded a new benchmark for evaluating the effectiveness of other Zika vaccine candidates, which could help others who are working toward the same goal. Dr. Jasdave Chahal, a postdoc at MIT’s Whitehead Institute for Biomedical Research, is the first author of the paper, which was published online on March 21, 2017 in Scientific Reports. The paper’s senior author is Dr. Hidde Ploegh, a former MIT biology professor and Whitehead Institute member who is now a senior investigator in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital. Other authors of the paper are Dr. Tao Fang and Dr. Andrew Woodham, both former Whitehead Institute postdocs in the Ploegh lab; Jingjing Ling, an MIT graduate student; and Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of the Koch Institute and MIT’s Institute for Medical Engineering and Science (IMES).

Panacea Pharmaceuticals Will Present Data That Its Cancer Biomarker HAAH Is Readily Detectable in Serum Exosomes

On March 30, 2017, Panacea Pharmaceuticals, Inc. announced that a paper regarding detection of the cancer biomarker HAAH [human aspartyl (asparaginyl) beta hydroxylase] will be presented at the annual American Association for Cancer Research (AACR) meeting in Washington, D.C., held April 1-5, 2017. The paper is titled: "Improved Detection of Cancer Specific Serum Exosomal Aspartyl (Asparaginyl) Beta Hydroxylase (HAAH)." The paper demonstrates major refinements to Panacea's multi-cancer HAAH-exosome detection assay that targets the cancer-specific blood serum biomarker HAAH. The cancer field is intensely focused upon exosomes, which are nanoparticle-sized sub-cellular vesicles derived from cancer cells that are proving to be important biomarkers and mediators of cancer cell metastasis and progression. The company asserts that the association of Panacea's target molecule HAAH with exosomes has led to a better individual understanding of these biomarkers as well as further development of a markedly improved diagnostic test with higher sensitivity and specificity than previous versions of the assay. "We are excited to report our continued advances in the understanding of the role of serum exosomes in the detection and monitoring of cancer," said Hossein Ghanbari, Ph.D., CEO and CSO of Panacea. Panacea Pharmaceuticals, headquartered in Gaithersburg, Maryland, is a clinical-stage biopharmaceutical company developing novel biologically targeted cancer therapies and diagnostics for unmet medical need.

New Study Establishes Evolutionary Origin of Photosynthesis in Cyanobacteria

The ability to generate oxygen through photosynthesis--that helpful service performed by plants and algae, making life possible for humans and animals on Earth--evolved just once, roughly 2.3 billion years ago, in certain types of cyanobacteria. This planet-changing biological invention has never been duplicated, as far as anyone can tell. Instead, according to “endosymbiotic theory,” all the "green" oxygen-producing organisms (plants and algae) simply subsumed cyanobacteria as organelles in their cells at some point during their evolution. "Oxygenic photosynthesis was an evolutionary singularity," says Woodward Fischer, Ph.D., Professor of Geobiology at Caltech, referring to the process by which certain organisms use the energy of sunlight to convert carbon dioxide and water into sugar for food, with oxygen as a by-product. "Cyanobacteria invented it, and then ultimately become the chloroplasts of algae. Plants are just a group of algae that moved on land." Yet, as world-shaping as cyanobacteria are, relatively little is known about them. Until a couple of decades ago, they were called "blue-green algae" by taxonomists, though it was later revealed that they are not algae at all, but rather a completely different type of organism. That lack of taxonomic understanding made deciphering the riddle of their evolution all but impossible, Dr. Fischer says. "For the longest time, they were just their own group. We had no answer about where they came from, or what other organisms they were related to," Dr. Fischer says. "Imagine trying to understand something about human evolution without knowledge of the great apes." Publishing in the March 31, 2017 issue of Science, Dr. Fischer and colleagues from Caltech and the University of Queensland in Australia have finally fleshed out cyanobacteria's family tree.

Scientists Model a Genetic Neurological Disease (PMD) with Oligodendrocytes Derived from Induced Pluripotent Stem Cells (iPSCs)

Researchers at the Case Western Reserve University School of Medicine in Cleveland have successfully grown stem cells from children with a devastating neurological disease to help explain how different genetic backgrounds can cause common symptoms. The work sheds light on how certain brain disorders develop, and provides a framework for developing and testing new therapeutics. Medications that appear promising when exposed to the new cells could be precisely tailored to individual patients based on their genetic background. In the new study, published online on March 30, 2017 in The American Journal of Human Genetics, researchers used stem cells in their laboratory to simultaneously model different genetic scenarios that underlie neurologic disease. They identified individual and shared defects in the cells that could inform treatment efforts. The open-access AJHG article is titled “Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes.” The researchers developed programmable stem cells, called induced pluripotent stem cells (iPSCs), from 12 children with various forms of Pelizaeus-Merzbacher disease (PMD). The rare, but often fatal, genetic disease can be caused by one of hundreds of mutations in a gene critical to the proper production of nerve cell insulation, or myelin. Some children with PMD have missing, partial, duplicate, or even triplicate copies of this gene, while others have only a small mutation. With so many potential causes, researchers have been in desperate need of a way to accurately and efficiently model genetic diseases like PMD in human cells. By recapitulating multiple stages of the disease in their laboratory, the researchers established a broad platform for testing new therapeutics at the molecular and cellular level.

Molecular Exchange Mediated by Microvesicles (MVs) Can Drive Acquisition of Phage Sensitivity by Normally Resistant Bacteria (R Cells) Co-Cultured with Infected Sensitive Bacteria (S Cells); Implications for Bacterial Genome Evolution

Scientists at The Hebrew University’s Institute of Medical Research Israel-Canada have made the unexpected observation that normally phage-resistant bacteria (R cells) can occasionally be invaded by phage when the R cells are cultured together with infected phage-sensitive bacteria (S cells). They termed this phenomenon “acquisition of sensitivity” (ASEN) and showed that it is mediated by the R cells transiently gaining phage attachment molecules from neighboring S cells. They further provided evidence that this molecular exchange is driven by microvesicles (MVs) containing phage attachment molecules that are released from infected S cells. The researchers suggest that this raises the possibility that such a mechanism facilitates transduction events among species by a plethora of phages, even by those having a narrow host range. They note that such multispecies transductions could prime horizontal gene transfer and, consequently, bacterial genome evolution. Phage invasion into R cells could have a major impact on the transfer of antibiotic resistance and virulence genes among bacteria. The scientists write that this possibility should be carefully considered when employing phage therapy, as phage infection of a given species may result in gene transmission into neighboring bacteria resistant to the phage. This research was published in the January 12, 2017 issue of Cell. The article is titled “Acquisition of Phage Sensitivity by Bacteria through Exchange of Phage Receptors.” Philip Askenase, M.D., Professor of Medicine & Pathology at the Yale University School of Medicine, made the following comment on the significance of this work: "Such a fundamental event in such a basic system by MVs speaks to their universality and the fundamental nature of their transfers." Dr. Askenase was not involved in the research.

March 29th

Fred Hutch Scientists Will Cover Advances in Immunotherapy & Proteomics at AACR Annual Meeting

Scientists from the Fred Hutchinson Cancer Research Center in Seattle, Washington are scheduled to present and discuss the latest developments in immunotherapy and proteomics at the American Association for Cancer Research (AACR) Annual Meeting “Research Propelling Cancer Prevention and Cures” April 1-5 in Washington, D.C. What follows here is a selection of the more than 30 Hutch presentations scheduled to be given at the AACR gathering. Dr. Kristin Anderson, a postdoctoral fellow in Dr. Philip Greenberg's lab at Fred Hutch, will present findings on a new adoptive T-cell therapy for ovarian cancer, a type of solid tumor with a very low survival rate and few new treatment options. Dr. Anderson and her colleagues engineered T-cells to recognize a protein overproduced on these cancer cells, and then tested the therapy on human ovarian cancer cells in the lab and in a mouse model of ovarian cancer. The findings showed that the T-cells killed human ovarian cancer cells and that the treatment extended the mice's survival. But the research also highlighted how the tumor microenvironment of ovarian cancer presents unique challenges to the therapy. Dr. Anderson and her colleagues have identified several roadblocks to T-cell therapy that are unique to solid tumors (as compared with blood cancers, where T-cell therapy has progressed farther toward clinical benefit) and will present strategies underway in the Greenberg lab to overcome those roadblocks with new therapies. Dr. Anderson is speaking on April 4 at 3:50 p.m. Her talk is titled, "Engineering Adoptive T-Cell Therapy for Efficacy In Ovarian Cancer." From the Human Genome Project onward, we've made a massive investment in science aimed at understanding human genomics.