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Archive - Jun 2013

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June 21st

First Example of Antibody-Coated-Exosome-Mediated T-Cell Regulation by Inhibitory miRNA Cargo

At the 2013 International Society for Extracellular Vesicles (ISEV) conference in Boston in mid-April, Philip Askenase, M.D., Professor of Medicine and Pathology, Section of Allergy and Immunology, Yale University School of Medicine, outlined work, done in full collaboration with scientists from the Jaggellonian University College of Medicine in Krakow, Poland, led by Krzysztal Bryniarski, Ph.D., that documented the first example of T-cell regulation by inhibitory miRNA passing from cell to cell via exosomes coated with antigen-specific antibody light chains and acting antigen-specifically in vivo in a systemic endocrine manner. With sequencing, Dr. Askenase’s group was able to identify the inhibitory miRNA as miRNA-150. Dr. Askenase said that, “this work offers new and novel approaches of antigen-specific T-cell regulation via transfer of genetic instructions to achieve entirely unique and new translational possibilities for the therapy of immunological and other diseases, including cancers. Exosomes can be activated for surface coating with the antibody of choice and easily transfected with the dsRNA of choice. The result is the construction of specifically tailored therapeutic exosomes as natural physiologic nanoparticles carrying miRNA of choice, delivered antigen-specifically to targeted cells via an antigen-specific antibody coating. This is simultaneous immunologic and genetic therapy with natural nanovesicles, and thus is termed nano immunogenetic therapy. These findings have great translational possibilities for treatment of various human diseases.” Dr. Askenase’s group’s exciting new work was published online on July 3, 2013 in the Journal of Allergy and Clinical Immunology for July 8, 2013. Dr.

June 17th

Genome Sequenicing Reveals Cause of Paracycling Champion’s Rare Condition

British National Paracycling Champion Tom Staniford has an extremely rare condition which, until now, has puzzled his doctors. He is unable to store fat under his skin – yet has type 2 diabetes – and suffered hearing loss as a child. Now, thanks to advances in genome sequencing, an international research team led by the University of Exeter Medical School has identified Tom's condition and pinpointed the single genetic mutation that causes it. As well as allowing a better understanding of Tom's condition, the discovery may have implications for his bid to participate in the Rio 2016 Paralympic Games. He hopes this new diagnosis will allow him to be more accurately classified in paracycling competitions; a more accurate classification could help him become a world champion. In a study published online on June 16, 2013 in Nature Genetics, researchers funded in part by the Wellcome Trust and the National Institute for Health Research have identified the genetic mutation behind MDP Syndrome, a condition thought to affect as few as eight people in the world, including 23-year-old Staniford. "In some ways, identifying the syndrome behind my symptoms shouldn't be important – a name is just a name, after all – but it is reassuring to know that there are other people with the condition and that we can lead relatively normal lives," says Staniford. "What could prove crucial, though, is enabling me to be properly classified in competitions so that I am not competing at an unfair disadvantage against others. I hope to be able to compete for Great Britain in the 2016 Paralympics and this finding could make a real difference to my chances." In 2011, Tom became the youngest solo cyclist ever to become British National Paracycling Circuit Race Champion.

GEN Covers Exosome Research on Front Page of June 15 Issue

Research on “exosomes” is the subject of the cover story of the June 15, 2013 issue of Genetic Engineering & Biotechnology News (GEN) (http://www.genengnews.com/). Exosomes are tiny subcellular membrane-bound vesicles (30-150 nm in diameter) that are released by a wide variety of normal cell types and cancer cells, and that can carry membrane and cellular proteins, as well as microRNA (miRNA), and various other types of RNA, including mRNA fragments, representative of the cell of origin. It is thought that exosomes may serve the purpose of shuttling information from one cell to another. For instance, it has been shown that exosomes can carry material from cancer cells that acts to suppress the immune system and stimulate angiogenesis, thus encouraging cancer growth. The GEN article covers some of the exciting research presented at the 2013 International Society for Extracellular Vesicles (ISEV) annual conference held in Boston, April 17-20. The article includes a discussion of Novartis’s Maja M.

June 15th

Exosomes, Deep Sequencing, and Biomarker Potential

At the 2013 annual International Society for Extracellular Vesicles (ISEV) (http://www.isevmeeting.org/) conference held in Boston, April 17-20, Michiel Pegtel, Ph.D., Immunologist in the Pathology Department at the VU University Medical Center in Amsterdam, The Netherlands, gave an oral presentation describing how comprehensive deep sequencing analysis revealed non-random small RNA incorporation into tumor exosomes and discussed the biomarker potential of these results. Exosomes (image) are tiny subcellular membrane-bound vesicles (30-150 nm in diameter) that are released by a wide variety of normal cell types and cancer cells, and that can carry membrane and cellular proteins, as well as microRNA (miRNA), and various other types of RNA, including mRNA fragments, representative of the cell of origin. It is thought that exosomes may serve the purpose of shuttling information from one cell to another. For instance, it has been shown that exosomes can carry material from cancer cells that acts to suppress the immune system and stimulate angiogenesis, thus encouraging cancer growth. In talking with BioQuick, Dr. Pegtel emphasized the key role of deep sequencing in his work. “In contrast to closed profiling technologies such as microarray and RT-PCR arrays, deep sequencing has literallyy opened our eyes on the complexity of the human transcriptome. Our previous work using individual quantitative RT-PCR could demonstrate that human B cells infected with the tumor virus Epstein Barr (EBV) secrete exosomes that contain fully mature and functional virus-encoded miRNAs. At the ISEV meeting, Nobel laureate Dr. Phillip Sharp stressed the importance of quantitation in RNA research. I could not agree more as this applies directly to research concerning transfer of functional RNA via exosomes.

Infectious Prions Are Associated with Morphologically Distinct Exosomes

At the 2013 annual International Society for Extracellular Vesicles (ISEV) (http://www.isevmeeting.org/) conference held in Boston, April 17-20, Andrew Hill, Ph.D., Professor in the Department of Biochemistry and Molecular Biology, at the Bio21 Institute, University of Melbourne in Australia, delivered an oral presentation entitled “Infectious Prions Are Associated with Morphologically Distinct Exosomes.” Exosomes (image) are tiny subcellular membrane-bound vesicles (30-150 nm in diameter) that are released by a wide variety of normal cell types and cancer cells, and that can carry membrane and cellular proteins, as well as microRNA (miRNA), and various other types of RNA, including mRNA fragments, representative of the cell of origin. It is thought that exosomes may serve the purpose of shuttling information from one cell to another. For instance, it has been shown that exosomes can carry material from cancer cells that acts to suppress the immune system and stimulate angiogenesis, thus encouraging cancer growth. In his presentation, Dr. Hill first showed evidence that PrPC (non-infectious) and PrPSc (infectious) forms of the prion protein are both associated with exosomes. He also demonstrated using cryo-electron microscopy that prion-infected cells release exosomes with distinct ultrastructural features and that prion-containing exosomes are more effective at transmitting prion infection than are cell extracts. Dr. Hill also showed that small RNA deep sequencing revealed a distinct miRNA profile in exosomes from prion-infected cells. This sequencing was carried out using the SOLiD® platform and also the Ion Torrent™ platform from Life Technologies. This analysis showed nine miRNAs to be dysregulated in the exosomes from prion-infected cells versus miRNAs in the exosomes from controls. Based on these results, Dr.

Molecule Boosts Memory in Mice

Memory was improved in mice injected with a small, drug-like molecule discovered by University of California-San Francisco (UCSF) researchers studying how cells respond to biological stress. The same biochemical pathway the molecule acts on might one day be targeted in humans to improve memory, according to the senior author of the study, Peter Walter, Ph.D., UCSF professor of biochemistry and biophysics and a Howard Hughes Investigator. The discovery of the molecule and the results of the subsequent memory tests in mice were published in eLife, an online scientific open-access journal, on May 28, 2013. In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of the potent chemical than mice that received sham injections. The mice that received the chemical also better remembered cues associated with unpleasant stimuli – the sort of fear conditioning that could help a mouse avoid being preyed upon. Notably, the findings suggest that despite what would seem to be the importance of having the best biochemical mechanisms to maximize the power of memory, evolution does not seem to have provided them, Dr. Walter said. "It appears that the process of evolution has not optimized memory consolidation; otherwise I don't think we could have improved upon it the way we did in our study with normal, healthy mice," Dr. Walter said. The memory-boosting chemical was singled out from among 100,000 chemicals screened at the Small Molecule Discovery Center at UCSF for their potential to perturb a protective biochemical pathway within cells that is activated when cells are unable to keep up with the need to fold proteins into their working forms.

glgS Gene Regulates Factors Involved in Bacterial Pathogenicity

In a piece of work carried out by the Carbohydrate Metabolism Research Team of the Institute of Agrobiotechnology (a center jointly owned by the NUP/UPNA-Public University of Navarre, the Spanish National Scientific Research Council-CSIC, and the Government of Navarre), the discovery has been made of the way in which the glgS gene (now renamed as the “surface composition regulator”, scoR) acts in bacteria and how the mechanisms involved in bacterial infection can be altered by manipulating this gene, which indirectly affects glycogen production. The finding has been protected through the application for a patent and the exploiting of it is now pending a response from institutions or companies prepared to develop it. Thanks to this discovery, the researchers received the top prize in the 9th International Medical Congress in the category of “Genetics and Molecular Biology” held in Warsaw recently. As Dr. Javier Pozueta, director of the Carbohydrate Metabolism Research Team that carried out the work, explained, "We can say that we may have found an additional way of combating bacterial infections and contamination by encouraging the formation of glycogen in bacteria. Now we know that by altering the glycogen-producing machinery, we can in turn alter the capacity of the bacteria to move, stick to a cell or to the surfaces of tubes, catheters, etc.” The 9th International Medical Congress held in Warsaw from 9 to 12 May, 2013, drew 1,400 researchers from all over the world and 700 pieces of work were presented. The researcher Dr. Mehdi Rahimpour attended on behalf of the research team of the Institute of Agrobiotechnology (IdAB). Together with Dr Manuel Montero, he was the main architect of the winning piece of research. The research was published online on March 28, 2013 in the Biochemical Journal and is based on the Ph.D.

June 14th

Skin Odor Analysis May Be Useful in Detection and Early Diagnosis of Melanoma

According to new research from the Monell Chemical Senses Center and collaborating institutions, odors from human skin cells can be used to identify melanoma, the deadliest form of skin cancer. In addition to detecting a unique odor signature associated with melanoma cells, the researchers demonstrated that a nanotechnology-based sensor could reliably differentiate melanoma cells from normal skin cells. The findings suggest that non-invasive odor analysis may be a valuable technique in the detection and early diagnosis of human melanoma. Melanoma is a tumor affecting melanocytes, skin cells that produce the dark pigment that gives skin its color. The disease is responsible for approximately 75 percent of skin cancer deaths, with chances of survival directly related to how early the cancer is detected. Current detection methods most commonly rely on visual inspection of the skin, which is highly dependent on individual self-examination and clinical skill. The current study took advantage of the fact that human skin produces numerous airborne chemical molecules known as volatile organic compounds, or VOCs, many of which are odorous. "There is a potential wealth of information waiting to be extracted from examination of VOCs associated with various diseases, including cancers, genetic disorders, and viral or bacterial infections," notes George Preti, Ph.D., an organic chemist at Monell who is one of the paper's senior authors. In the study, published in the July 15, 2013 issue of the Journal of Chromatography B, researchers used sophisticated sampling and analytical techniques to identify VOCs from melanoma cells at three stages of the disease, as well as from normal melanocytes. All the cells were grown in culture.

Same Gene Inhibits Breast Cancer and Strengthens Heart in Animal Model

Researchers at Case Western Reserve University have found that a single gene provides a double advantage against disease: Not only does it inhibit the growth and spread of breast tumors, but it also makes hearts healthier. In 2012, medical school researchers discovered the suppressive effects of the gene HEXIM1 on breast cancer in mouse models. Now they have demonstrated that it also enhances the number and density of blood vessels in the heart – a sure sign of cardiac fitness. Scientists re-expressed the HEXIM1 gene in the adult mouse heart and found that the hearts grew heavier and larger without exercise. In addition, the animals' resting heart rates decreased. The lowered heart rate indicates improved efficiency, and is supported by their finding that transgenic hearts were pumping more blood per beat. The team also discovered that untrained transgenic mice ran twice as long as those without any genetic modification. "Our promising discovery reveals the potential for HEXIM1 to kill two birds with one stone – potentially circumventing heart disease as well as cancer, the country's leading causes of death," said Monica Montano, Ph.D., associate professor of pharmacology, member of the Case Comprehensive Cancer Center, who created the mice for the heart and breast cancer research and one of the lead researchers in this study. Hypertension and subsequent heart failure are characterized by a mismatch between the heart muscles' need for oxygen and nutrients and blood vessels' inability to deliver either at the rate required. This deficit leads to an enlarged heart that, in turn, often ultimately weakens and stops. The researchers showed that increasing blood vessel growth through the artificial enhancement of HEXIM1 levels improved overall function – HEXIM1 may be a possible therapeutic target for heart disease.

Ancient and Modern Leprosy Bacterial Genomes Offer Insights into Disease History

From skeletons and biopsies, an international team of scientists has been successful in reconstructing a dozen medieval and modern genomes of the leprosy-causing bacteria Mycobacterium leprae. Under the direction of Professor Johannes Krause, University of Tübingen, and Professor Stewart Cole, Swiss Federal Institute of Technology of Lausanne (EPFL), the research group created a genome from archaeological finds for the first time without having to resort to a reference sequence. Professor Almut Nebel and Dr. Ben Krause-Kyora, both of the Institute of Clinical Molecular Biology, Kiel University, belong to the team, whose findings were published online on June 13, 2013 in Science magazine. Leprosy, a devastating infectious and chronic disease, was widespread in Europe until the Late Middle Ages. Persons infected with the disease were isolated in leprosy colonies specifically built for the patients. Today, the disease is found in 91 countries worldwide with more than 200,000 new infections per year. In order to trace the history of the disease, the scientists reconstructed the complete genomes of M. leprae from five medieval skeletons from Denmark, Sweden, and Great Britain. These specimens exhibited the characteristic bone changes associated with leprosy. Additionally, the M. leprae genetic substance was decoded from seven biopsy samples of contemporary patients. The researchers compared the European medieval M. leprae genome with those of the seven biopsies and four additional modern bacteria strains. They observed that all M. leprae strains have a common ancestor that existed less than 4,000 years ago. This result is supported by the earliest archaeological evidence of the disease in India.