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Archive - Sep 2015

September 15th

Scientists Find Genetic Clue to Treating Cancer Cachexia and Other Muscle-Wasting Syndromes of Disease & Aging

It is estimated that half of all cancer patients suffer from a muscle-wasting syndrome called cachexia. Cancer cachexia impairs quality of life and response to therapy, which increases morbidity and mortality of cancer patients. Currently, there is no approved treatment for muscle wasting, but a new study from the Research Institute of the McGill University Health Centre (RI-MUHC) and University of Alberta, both in Canada, could be a game-changer for patients, improving both quality of life and longevity. The research team discovered that a newly identified gene involved in muscle wasting could be a good target for drug development. The findings, which were published in September's print edition of the FASEB (Federation of American Societies for Experimental Biology) Journal could have huge clinical implications, as muscle wasting is also associated with other serious illnesses such as HIV/AIDS, heart failure, rheumatoid arthritis, and chronic obstructive pulmonary disease, and is also a prominent feature of aging. "We discovered that the gene USP19 (coding for ubiquitini-specific protease 19 debiquitinating enzyme) appears to be involved in human muscle wasting and that in mice, once inhibited, it could protect against muscle wasting,” says lead author Dr. Simon Wing, MUHC endocrinologist and Professor of Medicine at McGill University. "Muscle wasting is a huge unmet clinical need. Recent studies show that muscle wasting is much more common in cancer than we think." In the current study, researchers worked with mice models that were lacking USP19 (i.e., USP19 KO) and decided to look at two common causes of muscle wasting.

Nearly Forgotten 80-Year-Old Tissue Allograft Method for Transplanting Fly Tissue Resurrected, Enables Resurgent Study of Tissue Regeneration and Tumor Growth in Drosophila

A study conducted by ICREA (Catalan Institution for Research and Advanced Studies) researcher Dr. Cayetano González, at the Institute for Research in Biomedicine (IRB Barcelona), and published online on September 10, 2015 in Nature Protocols describes a virtually forgotten technique used in the fly Drosophila melanogaster dating back 80 years. This method allows the transplantation of tissue from larvae to adult flies, thus allowing research into tumor growth and other biological processes of biomedical interest, such as tissue regeneration. The article is titled “Studying Tumor Growth in Drosophila Using the Tissue Allograft Method.” In 2002, Dr. González, head of the Cell Division lab at IRB Barcelona, faced a major technical problem with respect to research into tumor growth in Drosophila, namely the limitless growth of malignant tumours, which kill the fly. The solution seemed straightforward—tumor transplants, a common technique used in cancer research in mammals, including humans, which involves the transplantation of the tumor mass to mice. With over a century of research into the fly, it was hoped that the many tools available for this model would include one for tissue transplants. “And this was indeed the case, but the articles devoted to methodologies were few and incomplete and therefore reproducing the technique in the lab was very complicated,” explains Professor González. Developed in 1935, the technique was used extensively in the following decades and then fell into disuse and practically disappeared towards the end of the last century. “In 2002, only a small number of researchers worldwide were aware of the existence of the technique,” he says. Professor János Szabad, from the University of Szeged, in Hungary, was one of the few who continued to use the method and he invited Dr.

Japanese Chemists Achieve Enantioselective Phenoxylation of β-Keto Esters; Novel Method Allows Synthesis of α-Aryloxy-β-Keto Esters with High Enantioselectivity; Compounds Already Synthesized for Potential Treatment of Type 2 Diabetes

Aryl alkyl ethers are important structural motifs found in many biologically active compounds. Therefore, stereoselective etherification is a highly important synthetic operation in the preparation of drug candidates. However, very few enantioselective methods have been described for the synthesis of chiral tertiary aryl ethers. Researchers at Toyohashi Tech in Japan have now found that the SN2 reaction of α-chloro-β-keto esters with phenols proceeded smoothly, despite the fact that the reaction occurred at a tertiary carbon [1]. The scientists previously reported the highly enantioselective chlorination of β-keto esters with a chiral Lewis acid catalyst [2]. Thus, in the two investigations, the researchers have successfully demonstrated the enantioselective phenoxylation of β-keto esters. The novel presented method allows the synthesis of α-aryloxy-β-keto esters with high enantioselectivity. "Etherification by the SN2 reaction is an older synthetic method called Williamson ether synthesis, but very few researchers have succeeded in conducting this reaction with tertiary halides," said Associate Professor Kazutaka Shibatomi. “This is the first example of the enantioselective synthesis of α-aryloxy-β-keto esters, which would be useful synthetic intermediates for new drug candidates." Using this method, the researchers have already demonstrated the synthesis of some biologically active compounds, including a GPR119 agonist and a PPARγ (image) modulator, for the potential treatment of type 2 diabetes. The researchers expect that the present method will also be helpful in preparing other types of synthetic drugs.

BRD4 Inhibitors, AML, Enhancers; Cancer Vulnerability to BRD4 Inhibition Enhanced by Weak WNT Signaling; Loss of PRC2 Complex Increases Cancer Resistance to BRD4 Inhibition

BRD4 inhibitors are among the most promising new agents in cancer therapy and they are currently being evaluated in clinical trials. BRD4 is a member of the BET (bromo- and extra-terminal (BET) family of proteins: BRD2 (bromodomain-containing protein 2), BRD3 (bromodomain-containing protein 3), and BRD4 (bromodomain-containing protein 4). In a study published online on September 14, 2015 in Nature, a team of researchers at the Research Institute of Molecular Pathology (IMP) and Boehringer Ingelheim. both in Vienna, Austria reveals how leukemia cells can evade the deadly effects of BRD4 inhibition. The article is titled “Transcriptional Plasticity Promotes Primary and Acquired Resistance to BET Inhibition.” Understanding this adaptation process could aid the development of sequential therapies to outsmart resistant leukemias. Over the past years, scientists have drawn an almost complete map of mutations in cancer. However, translating complex genetic knowledge into effective cancer therapies turns out to be a major challenge for modern medicine. Searching for new ways to attack cancer cells, the laboratory of Dr. Johannes Zuber at the IMP in Vienna uses so-called functional genetic screens to probe vulnerabilities of cancer cells in a systematic and unbiased way. The major goal is to find genes that cancer cells particularly depend on, and then exploit these “Achilles’ heels” for the development of targeted therapies. In a first study applying this technology, Dr. Zuber and his former colleagues at Cold Spring Harbor Laboratory (CSHL) (New York) in 2011 found that the gene BRD4 is such an “Achilles’ heel” in acute myeloid leukemia (AML), an aggressive form of blood cancer.

First-Draft Genome Sequence of Tiger Mosquito Determined, Insect Transmits Dengue Fever and Chikungunya Fever, and Other Deadly Diseases, Infecting Millions Annually

On September 14, 2015, Pathogens and Global Health journal published online, in an open-access article, details of the first-draft genome sequence of Aedes albopictus, commonly known as the tiger mosquito and responsible for transmitting several deadly diseases to humans, such as dengue fever and chikungunya fever, both carried by viruses, potentially offering hope to millions around the world. "This sequencing…offers great hope to our understanding of the mosquito and our ability to control it, potentially saving millions of lives in many areas of the world," said Professor Andrea Crisanti, Editor-in-Chief of Pathogens and Global Health. The Pathogens and Global Health article provides a first look into the genetics of a most dangerous and invasive insect and the possibility of developing ways to prevent the spread of the dengue and chikungunya fevers that infect millions of people annually. The advance is all the more urgent now, given increasingly high levels of mosquito migration and the fact that Aedes albopictus has been moving in recent years from its natural habitats in tropical South East Asia to many parts of the world, including Europe, the United States, and Africa. It is estimated that as many as 400 million people are infected by the dengue and chikungunya viruses carried by the tiger mosquito and transmitted to people as it feeds on their blood. The article is titled “A Draft Genome Sequence of an Invasive Mosquito: an Italian Aedes albopictus.” Major global upheavals have undoubtedly contributed to the large-scale spread of Aedes albopictus, and these are believed to include climate change, urbanization of rural areas, and, indeed, changes in the use of land itself. This has all led to fears among many populations of a risk of infection from Aedes albopictus.

September 14th

Utilizing the Technical Advantages of Hollow-Fiber Bioreactor Technology for the Continuous Production of Exosomes (by William Whitford, John W. Ludlow, Ph.D., and John J.S. Cadwell)

[BQ Editor’s Note: This article is reproduced here in its entirety with the express permission of the original publisher Genetic Engineering & Biotechnology News (GEN). The GEN publication date was September 15, 2015. A Figure and two tables have been removed and readers should refer to the original GEN article to review the details of these graphic elements, The GEN artricle can be found at the following link:] Interest in exosomes has grown of late, particularly because these sub-cellular vesicles have been seen to take part in functional interactions with antigen-presenting cells, and in the modulation of the immune response in vivo. For example, tumor exosomes are thought to participate in metastasis of tumor cells, seeding tumor-draining lymph nodes prior to tumor cell migration, and increasing their motility. These nanovesicles have already proven themselves as having such therapeutic potential as the repair of cardiac tissue after heart attack, which had been axiomatically unheard prevoiously in the annals of cardiology. Clinical trials for many indications, such as using dendritic cell-derived exosomes to facilitate immune response to cancers, are now underway. As their content is a fingerprint of the type and status of the cell generating them, the prognostic potential of exosomes as biomarkers, including biomarkers that could be used to predict cell therapy outcome, is being explored. Current work on exosome manufacturing involves their regulatory-compliant generation in an appropriate cell line and separation from such process-related contaminants as other extracellular vesicles.

BioQuick Publisher Discusses Clinical Adoption of LC-MS/MS at JASIS 2015 Analytical Instrument Conference in Japan, Largest Such Meeting in Asia and Perhaps in World; Record 25,000 Attend This Year’s Three-Day Meeting Just Outside Tokyo

BioQuick Editor & Publisher Michael D. O’Neill had the distinct honor of being asked to give a presentation at this year’s Japan Analytical Scientific Instruments Show (JASIS 2015), held September 2 though September 4, in Chiba, Japan, a city located just outside Tokyo. Unbeknownst to many, this annual analytical instruments show is by far the largest held in Asia, and it is perhaps now the largest held in the world, as Pittcon, a U.S.-based conference that once held that status has had somewhat diminished attendance in recent years. Estimates of this year’s JASIS attendace were on the order of 25,000, the largest ever. There were an estimated 500 exhibitors and approximately 1,500 booths. The many exhibitors included Shimadzu, ThermoFisher Scientific, Agilent Technologies, Bruker, Perkin-Elmer Japan, Hitachi High-Tech Science Corporation, JEOL Ltd., Sciex, and Merck, among many others. Some 360 topics in New Technology were presented by exhibitors and approximately 50 conferences were conducted by academic and research organizations. The conference was jointly organized by the Japan Analytical Instruments Manufacturers’ Association and the Japan Scientific Instruments Association. Leaders of these two organizations are Gon-emon Kurihara, President, Japan Analytical Instruments Manufacturers’ Association, President and Representative Director, JEOL, Ltd.; and Hideto Yazawa, Chairman, Japan Scientific Instruments Association, Chairman, Dalton Co., Ltd. As an eye-witness to this incredibly well-organized event, I can only say “hats off” to these leaders who really made the incredible happen. Interestingly, to this first-time visitor to Japan, almost all the conference presentations were delivered in Japanese, with just a few, like mine, delivered in English and simultaneously translated into Japanese over headsets.

Rutgers Scientists Combine Several Capabilities for First Time in Device Called “ELISA-on-a-Chip;” Predicted to Slice Cost of Lab Tests for Wide Range of Disorders, Including HIV, Lyme Disease, and Syphilis; Requires 90% Less Fluid Than Current Tests

Rutgers engineers have developed a breakthrough device that can significantly reduce the cost of sophisticated lab tests for medical disorders and diseases, such as HIV, Lyme disease, and syphilis. The new device uses miniaturized channels and valves to replace "benchtop" assays - tests that require large samples of blood or other fluids and expensive chemicals that lab technicians manually mix in trays of tubes or plastic plates with cup-like depressions. "The main advantage is cost - these assays are done in labs and clinics everywhere," said Dr. Mehdi Ghodbane, who earned his doctorate in biomedical engineering at Rutgers and now works in biopharmaceutical research and development at GlaxoSmithKline. Dr. Ghodbane and six Rutgers researchers first published their results online on June 23, 2015 in the Royal Society of Chemistry's journal, Lab on a Chip. The article is titled “Development and Validation of a Microfluidic Immunoassay Capable of Multiplexing Parallel Samples in Miicroliter Volumes.” The lab-on-chip device, which employs microfluidics technology, along with making tests more affordable for patients and researchers, opens doors for new research because of its capability to perform complex analyses using 90 percent less sample fluid than needed in conventional tests. "A great deal of research has been hindered because in many cases one is not able to extract enough fluid," Ghodbane said. The Rutgers breakthrough also requires one-tenth of the chemicals used in a conventional multiplex immunoassay, which can cost as much as $1500. Additionally, the device automates much of the skilled labor involved in performing tests. "The results are as sensitive and accurate as the standard benchtop assay," said Dr.

Hitachi Announces System for Exosome Collection Leading to mRNA Purification

On Septemeber 1, 2015, Hitachi Chemical Diagnostics, Inc. announced the availability of the ExoComplete™ 96-Well Plate Kit and ExoComplete™ Tube Kit, an integrated, fast, and easy system for exosome collection to mRNA purification. Both products are intended for research use only of molecular biology applications and are neither intended for the diagnosis, prevention, or treatment of a disease, nor has either been validated for such use either alone or in combination with other products. The ExoComplete™ system isolates exosomal mRNA from biological samples such as plasma in a 96-well filter plate format(1), or large-volume samples such as urine in a single collection tube format(2). Exosomes and microvesicles (EMVs) in body fluids are captured with Hitachi Chemical's Exosome Isolation Plate or Exosome Collection Tube with a proprietary filter material. The highly porous material allows fast filtration of biological samples without clogging, and reproducible isolation of EMVs without the use of conventional ultracentrifugation. After lysing the captured EMVs, mRNA can be isolated through hybridization with single-strand oligo (dT) immobilized in the wells of the 96-well mRNA Capture Plate. A wide variety of downstream applications become available following isolation of mRNA, including mRNA quantification, single and double-stranded cDNA synthesis, RT-PCR, real time quantitative RT-PCR (qPCR), and next-generation RNA sequencing. Hitachi Chemical Diagnostics, Inc., a division of Hitachi Chemical Company America, Ltd., Cupertino, California is headquartered in the heart of Silicon Valley in Mountain View, California, and is a global leader of multiplex in vitro allergy diagnostics. The company works with industry leaders, laboratories, and distributors in more than 40 countries.

Pecking Order in Monk Parakeets Appears to be Determined by Cognitive Reasoning After Watching Bouts Between Other Monk Parakeets

A study of aggression in monk parakeets suggests that where they stand in the pecking order is a function of the bird's carefully calibrated perceptions of the rank of their fellow-feathered friends. Newly formed groups of monk parakeets do not show evidence that they perceive rank, yet an awareness of it emerges quickly, after about a week of interactions, which is when individuals direct aggression more frequently against those nearby in rank rather than with lower-ranked birds. But how do the birds infer rank - their own and the rank of those in the rest of the flock - and then act upon it? "Parakeets appear to be able to connect the dots in their groups, remembering chains of aggression, so if A fights B, then watches how B fights C and how C fights D and how D fights E, then A will use this knowledge to adjust how it interacts with E based on all of the fights in between," said the study's lead author Dr. Elizabeth Hobson, a postdoctoral fellow at the National Institute for Mathematical and Biological Synthesis in the USA. The study published on September 10, 2015 in the open-access journal PLOS Computational Biology sheds new light on how socially complex animal societies evolve and how dominance hierarchies are established. The article is titled “Social Feedback and the Emergence of Rank in Animal Society."A socially and cognitively complex species, monk parakeets inhabit a social structure organized by dominance hierarchies, such that each animal is ranked as dominant over animals below it and submissive to those above it in the hierarchy. Aggressive encounters usually drive rankings, and a higher rank, of course, often means better foraging opportunities and greater chances of reproductive success.