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EXOSOME NEWS: Avalon GloboCare Teams with Weill Cornell Medicine to Co-Develop Standardization of cGMP-Grade Exosome Isolation and Application of Tissue-Specific Exosomes

On October 9, 2018, Avalon GloboCare Corp. (OTCQB: AVCO), a leading global developer of cell-based technologies and therapeutics, headquartered in New Jersey, USA, announced that Weill Cornell Medicine has selected its subsidiary Genexosome Technologies’ proprietary exosome isolation system as a key component in the world’s first standardization processing of cGMP-grade exosomes for clinical studies. This co-development program is led by Yen-Michael Hsu, MD, PhD, Director of cGMP Cellular Therapy Facility and Laboratory for Advanced Cellular Engineering at Weill Cornell. This co-development program will focus on two main objectives: (1) standardization of cGMP-grade exosome isolation from human endothelial cells, essential for vascular health and organ regeneration; and (2) identification and isolation of tissue-specific exosomes for liquid biopsy and clinical use. A material transfer agreement will accompany this announcement to facilitate and authorize the use of GenExosome’s isolation system by Weill Cornell. “Identification and isolation of tissue-specific exosomes is considered by many as the “Holy Grail” in this area. This co-development and standardization initiative with Weill Cornell has further enhanced the global recognition, intellectual property, as well as our leading role in this industry sector,” stated Yu Zhou, MD, PhD, Founder and Co-CEO of GenExosome Technologies, Inc. "This strategic co-development endeavor will synergize Genexosome Technologies’ top-rated isolation platform with Weill Cornell’s world-class cGMP cellular therapy/cell-derived product processing facility to accelerate innovative exosome technology development, as well as standardization in clinical-grade exosome bio-production process,” stated David Jin, MD, PhD, CEO and President of Avalon GloboCare Corp.

Two Genes Responsible for Remarkable Difference in Flower Color of Nearby Snapdragons Identified; Islands of Divergence Established by Gene Flow & Multiple Selective Sweeps; Bee Pollination a Key Factor

Snapdragons are charming tall plants that flower in a range of bright colors. In Spain, where snapdragons grow wild, these flower colors show a remarkable pattern: When driving up a road from Barcelona to the Pyrenees, snapdragons of the species Antirrhinum majus bloom in magenta at the beginning of the road, before a population of yellow flowering snapdragons takes over - separated by just a two kilometer c long stretch in which flower colors mix. Such hybrid zones of snapdragons are quite infrequent; only a few others are known. But why don't the snapdragons mix, with yellow and magenta flowers growing together over a wide area? Dr. Nick Barton at the Institute of Science and Technology Austria (IST Austria), together with Dr. David Field, previously a postdoc in Dr. Barton's group and now Assistant Professor at the University of Vienna, collaborated with molecular geneticists at the John Innes Center in Norwich, UK, to investigate the causes of this pattern. In an article published online on October 8, 2018 in PNAS, the scientists report that they identified the genes responsible for flower color difference from DNA sequence data. The open-access article is titled “Selection and Gene Flow Shape Genomic Islands That Control Floral Guides.” "DNA sequencing is becoming cheaper and cheaper. But analyzing sequence data and interpreting the patterns seen is very hard,” Dr. Barton explains. “In this study, we used sequence data from Antirrhinum plants to locate the individual genes that are responsible for the difference in flower color across the hybrid zone." The researchers compared the genome sequences of 50 snapdragons of each color, and measured how much the sequences diverged between magenta and yellow snapdragon populations.

Phenylketonuria Cured in Mouse Model by Adaptation of CRISPR/Cas9 Gene Editing—60% Gene Correction Rate Achieved Employing Base Editor Cytidine Deaminase

Parents of newborns may be familiar with the metabolic disorder phenylketonuria: in Switzerland, all newborn babies are screened for this genetic disease. If a baby is found to have phenylketonuria, he or she requires a special diet so that the amino acid phenylalanine does not accumulate in the body. Excess phenylalanine delays mental and motor development. If left untreated, the children may suffer massive mental disability. The cause of this metabolic disorder is a mutation in a gene that provides the blueprint for the enzyme phenylalanine hydroxylase (Pah). This enzyme, which is produced by the cells of the liver, metabolizes phenylalanine. The disorder is referred to as "autosomal recessive"--the child develops the disease if he or she inherits one mutated Pah gene from the mother and one from the father. There has been no cure for this disorder to date. A team of researchers led by ETH Zurich professor Gerald Schwank has now taken advantage of a method to correct both mutated genes in the liver cells and thus heal the disease. (Editor’s Note: ETH Zurich is a science, technology, engineering, and mathematics university in the city of Zürich, Switzerland.) Dr. Schwank’s team has succeeded, at least in mice. With the help of a CRISPR/Cas9 system extended by one enzyme, the researchers changed the sequence of the DNA building blocks for the Pah corresponding gene in adult mice. The mouse liver cells were subsequently able to produce functioning Pah enzymes, and the mice were healed. The work was reported online on October 8, 2018 in Nature Medicine. The article is titled “Treatment of a Metabolic Liver Disease by In Vivo Genome Base Editing in Adult Mice.” Following are more details on the work.

New Nanopore System Can Detect Multiple Small Molecules in Nanoliter of Biological Fluids Quickly and Simultaneously; May Lay Foundation for Disruptive New Technology for Medical Diagnostics

University of Groningen (Netherlands) scientists, led by Associate Professor of Chemical Biology Giovanni Maglia, have designed a nanopore system that is capable of measuring different metabolites simultaneously in a variety of biological fluids, all in a matter of seconds. The electrical output signal is easily integrated into electronic devices for home diagnostics. The results were published online on October 5, 2018 in Nature Communications. The open-access article is titled “Direct Electrical Quantification of Glucose and Asparagine from Bodily Fluids Using Nanopores.” Measuring many metabolites or drugs in the body is complicated and time-consuming, and real-time monitoring is not usually possible. The ionic currents that pass through individual nanopores are emerging as a promising alternative to standard biochemical analysis. Nanopores are already integrated into portable devices to determine DNA sequences. “But it is basically impossible to use these nanopores to specifically identify small molecules in a complex biological sample,” says Dr. Maglia. A year ago, Dr. Maglia and colleagues demonstrated how to use nanopores to identify the “fingerprints” of proteins and peptides, and even to distinguish polypeptides that differ by one amino acid (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715100/). Now, he has adapted this system to identify small molecules in biological fluids. To do so, he used a larger cylindrical-shaped nanopore to which he added substrate-binding proteins. “Bacteria make hundreds of these proteins to bind substrates in order to transport them into the cells. These proteins have specificities that have evolved over billions of years.” Dr. Maglia adapts the binding proteins to fit inside the nanopore. If a protein then binds to its substrate, it changes its conformation.

2018 Chemistry Nobel Awarded for Directed Evolution of Enzymes & Phage Display

On October 3, 2018, The Royal Swedish Academy of Sciences announced that it had decided to award the Nobel Prize in Chemistry 2018 with one half to Dr. Frances H. Arnold (photo), California Institute of Technology, Pasadena, USA, “for the directed evolution of enzymes,” and the other half jointly to George P. Smith, University of Missouri, Columbia, USA, and Sir Gregory P. Winter, MRC Laboratory of Molecular Biology, Cambridge, UK, “for the phage display of peptides and antibodies.” The power of evolution is revealed through the diversity of life. The 2018 Nobel Laureates in Chemistry have taken control of evolution and used it for purposes that bring great benefit to humankind. Enzymes produced through directed evolution are used to manufacture everything from biofuels to pharmaceuticals. Antibodies evolved using a method called phage display can combat autoimmune diseases and, in some cases, cure metastatic cancer. Since the first seeds of life arose approximately 3.7 billion years ago, almost every crevice on Earth has filled with different organisms. Life has spread to hot springs, deep oceans and dry deserts, all because evolution has solved a number of chemical problems. Life’s chemical tools – proteins – have been optimized, changed and renewed, creating incredible diversity. This year’s Nobel Laureates in Chemistry have been inspired by the power of evolution and used the same principles – genetic change and selection – to develop proteins that solve mankind’s chemical problems. One half of this year’s Nobel Prize in Chemistry is awarded to Dr. Arnold. In 1993, she conducted the first directed evolution of enzymes. Since then, she has refined the methods that are now routinely used to develop new catalysts. The uses of Dr.

Natural Product (Fisetin) Found to Extend Healthspan in Animal Model; Mass Spec Technique Shows Effects on Specific Subsets of Cells

Previous research published earlier this year in Nature Medicine (https://www.nature.com/articles/s41591-018-0092-9) involving University of Minnesota Medical School faculty Dr. Paul D. Robbins and Dr. Laura J. Niedernhofer and Mayo Clinic investigators Dr. James L. Kirkland and Dr. Tamara Tchkonia, showed it was possible to reduce the burden of damaged cells, termed senescent cells, and extend lifespan and improve health, even when treatment was initiated late in life. They now have shown that treatment of aged mice with the natural product fisetin (image), found in many fruits and vegetables, also has significant positive effects on health and lifespan. As people age, they accumulate damaged cells. When the cells get to a certain level of damage they go through an aging process of their own, called cellular senescence. The cells also release inflammatory factors that tell the immune system to clear those damaged cells. A younger person's immune system is healthy and is able to clear the damaged cells. But, as people age, these damaged cells aren't cleared as effectively. Thus, they begin to accumulate, cause low level inflammation, and release enzymes that can degrade tissue. Dr. Robbins and fellow researchers found that a natural product, called fisetin, reduces the level of these damaged cells in the body. They found this by treating mice towards the end of life with this compound and seeing improvement in health and lifespan. The open-access article, "Fisetin Is a Senotherapeutic That Extends Health and Lifespan," was published on September 29, 2018 in EBioMedicine. "These results suggest that we can extend the period of health, termed healthspan, even towards the end of life," said Dr. Robbins. "But there are still many questions to address, including the right dosage, for example."

Miniature Magnetic Swimming Devices May Revolutionize Diagnostics and Drug Delivery; Devices Can Be Made on Industrial Scale

Scientists have created miniature magnetic swimming devices - which mimic the appearance of sperm cells - that could revolutionize disease treatment by ferrying drugs to specific areas of the body. The devices, which measure as small as one millimeter long, consist of a magnetic head and flexible tail that allows them to “swim” to a specific location when activated by a magnetic field. Researchers at the University of Exeter in the UK, who designed the devices and magnetic control mechanism, have also created a mathematical model that allows them to predict the devices’ behavior in different environments, such as microfluidic channels or complex liquids. The researchers believe that the devices could be used to deliver drugs to specific areas of the body, thus potentially dramatically improving treatment time and success. The scientists also believe that the devices could revolutionize the wider field of microfluidics, which focuses on moving liquids through extremely narrow channels. The team’s research is currently focused on implementing microscopic prototypes and the researchers have already successfully demonstrated swimmers comparable to the size of red blood cells. The research was published recently in the Physics of Fluids journal. Professor Feodor Ogrin, principal investigator at the University of Exeter said: "Developing this technology could radically change the way we do medicine. The swimmers could one day be used to direct drugs to the right areas of the body by swimming through blood vessels. We also envisage microscopic versions of the device being used on 'lab-on-a-chip' technology, where complex procedures normally conducted in a laboratory, such as diagnosing disease, are conducted on a simple chip.

Study Finds That Ornithine Decarboxylase Inhibitor DFMO Increases Survival for Children with High-Risk Neuroblastoma

A paper published online on September 27, 2018 in Scientific Reports shows the positive results of a phase II clinical trial using the oral medication DFMO (difluoromethylornithine) to prevent relapse in children with high-risk neuroblastoma (HRNB). The open-access article is titled “Maintenance DFMO Increases Survival in High Risk Neuroblastoma.” Neuroblastoma is a form of cancer that develops from immature nerve cells found in several areas of the body. It occurs most often in infants and young children, usually under the age of five. The disease remains a challenge in pediatric oncology and current treatments include therapies that have significant long-term side effects for patients. HRNB accounts for 15 percent of all childhood cancer deaths, in part, due to the fact that nearly half of all patients who reach remission will relapse. "These results are promising and have changed the outlook for our patients with high risk neuroblastoma," said Giselle Sholler, MD, Director of Pediatric Oncology Research at Spectrum Health Helen DeVos Children's Hospital in Grand Rapids, Michigan, and principal investigator of the study. "By using DFMO for two years after finishing conventional therapy, we've seen an overall two-year survival rate for these children of 97 percent. This is a large increase in survival," Dr. Sholler added. "Previously it was believed that children with refractory and relapsed neuroblastoma were considered incurable. This study shows more than 50 percent of patients remaining in remission up to four years." The trial, organized by the Beat Childhood Cancer research consortium, studied the use of DFMO as a single agent for enrolled patients at 20 children's hospitals from June 2012 to February 2016.

Scientists Show “Proof of Principle” with Recombinant Human Antibody Panel Against Snake Venom (Black Mamba)

On October 2, 2018, IONTAS Limited, a leader in the discovery and optimization of fully human antibodies, today announced a collaborative paper published in Nature Communications1 with the Technical University of Denmark (DTU), and the Instituto Clodomiro Picado of the University of Costa Rica describing the development of a panel of human antibodies that neutralize elements of black mamba snake toxin in an in vivo model. The open-access article, published online on October 2, 2018, is titled “In Vivo Neutralization of Dendrotoxin-Mediated Neurotoxicity of Black Mamba Venom By Oligoclonal Human Igg Antibodies.” Each year, approximately two million people fall victim to snakebite envenoming, which leads to more than 100,000 deaths and approximately 400,000 cases of severe sequalae, such as amputation. Particularly, impoverished victims living in snake-infested areas of the tropics are at risk, and many bites are left untreated due to the unavailability of safe and effective antivenoms. Snakebite envenoming has recently been introduced on the World Health Organization’s list of neglected tropical diseases due to its high disease burden. The “proof of concept” research described in the Nature Communications article identified key components, including dendrotoxins, in the black mamba’s venom that contribute to venom toxicity. Human antibodies were generated to these dendrotoxins using IONTAS Phage Display Technology and cocktails of IgG-formatted human antibodies were then shown to protect mice from dendrotoxin-mediated neurotoxicity in vivo.

Nobel Prize Awarded for Checkpoint Inhibitors-Tumor Immunology

The Nobel Assembly at Karolinska Institutet has today (October 1, 2018) announced its decision to award the 2018 Nobel Prize in Physiology or Medicine jointly to Dr. James P. Allison and Dr. Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation.” Cancer kills millions of people every year and is one of humanity’s greatest health challenges. By stimulating the inherent ability of our immune system to attack tumor cells this year’s Nobel laureates have established an entirely new principle for cancer therapy. Dr. Allison studied a known protein that functions as a brake on the immune system. He realized the potential of releasing the brake and thereby unleashing our immune cells to attack tumors. He then developed this concept into a brand new approach for treating patients. In parallel, Dr. Honjo discovered a protein on immune cells and, after careful exploration of its function, eventually revealed that it also operates as a brake, but with a different mechanism of action. Therapies based on his discovery proved to be strikingly effective in the fight against cancer. Dr. Allison and Dr. Honjo showed how different strategies for inhibiting the brakes on the immune system can be used in the treatment of cancer. The seminal discoveries by the two laureates constitute a landmark in our fight against cancer. Cancer comprises many different diseases, all characterized by uncontrolled proliferation of abnormal cells with capacity for spread to healthy organs and tissues. A number of therapeutic approaches are available for cancer treatment, including surgery, radiation, and other strategies, some of which have been awarded previous Nobel Prizes.

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