Syndicate content

Archive

September 21st, 2017

Exosomes May Be Missing Link to Insulin Resistance in Diabetes

Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked, until now. In a paper, published in the journal Cell on September 21, 2017, University of California San Diego School of Medicine researchers identified exosomes — extremely small vesicles or sacs secreted from most cell types — as the missing link. The article is titled “Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity.” “The actions induced by exosomes as they move between tissues are likely to be an underlying cause of intercellular communication causing metabolic derangements of diabetes,” said Jerrold Olefsky, MD, Professor of Medicine in the Division of Endocrinology and Metabolism at UC San Diego School of Medicine and senior author of the paper. “By fluorescently labeling cells, we could see exosomes and the microRNA they carry moving from adipose (fat) tissue through the blood and infiltrating muscle and liver tissues.” During chronic inflammation, the primary tissue to become inflamed is adipose tissue. Forty percent of adipose tissue in obesity is comprised of macrophages — specialized immune cells that promote tissue inflammation. Macrophages in turn create and secrete exosomes. When exosomes get into other tissues, they use the microRNA (miRNA) they carry to induce actions in the recipient cells. The macrophage-secreted miRNAs are on the hunt for messenger RNAs. When the miRNA finds a target in RNA, it binds to it, rendering the messenger RNA inactive. The protein that would have been encoded by the messenger RNA is no longer made. Thus, the miRNAs are a way to inhibit the production of key proteins. A team led by Dr.

Tumor-Associated Macrophages (TAMs) Promote Neuroblastoma by STAT3 Phosphorylation and Up-Regulation of c-MYC

Investigators at the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles have reported new findings about an immune cell - called a tumor-associated macrophage - that promotes cancer instead of fighting it. They have identified the molecular pathway, known as STAT3, as the mechanism the immune cell uses to foster neuroblastoma, a pediatric cancer, and have demonstrated use of a clinically available agent, ruxolitinib, to block the pathway. Results of the study were published online in Oncotarget on September 20, 2017. The article is titled Tumor-Associated Macrophages Promote Neuroblastoma Via STAT3 Phosphorylation and Up-Regulation of c-MYC.” Neuroblastoma is the second most common solid tumor effecting children. Individuals with high-risk disease have a mortality rate of approximately 50 percent. Certain conditions are associated with high-risk disease. High levels of some chemicals involved with inflammation and the presence of an immune cell called a tumor-associated macrophage (TAM) are associated with high-risk disease and lower survival rates. Macrophages are a type of immune cell that typically function to battle disease, not encourage it. "The macrophages are essentially co-opted by the tumor cells to help them grow," said Shahab Asgharzadeh, MD, Director of the Basic and Translational Neuroblastoma program at CHLA and lead investigator of the study. "We're trying to find out more about the mechanisms that enable TAMs to help cancer grow so that we can target the pathways they use and block their pro-tumor effect."

Discovery by Doudna Lab & Collaborators Should Help Improve Accuracy of CRISPR-Cas9 Gene Editing

Scientists at the University of California, Berkeley, and Massachusetts General Hospital have identified a key region within the Cas9 protein that governs how accurately CRISPR-Cas9 homes in on a target DNA sequence, and have tweaked it to produce a hyper-accurate gene editor with the lowest level of off-target cutting to date. The protein domain the researchers identified as a master controller of DNA cutting is an obvious target for re-engineering to improve accuracy even further, the researchers say. This approach should help scientists customize variants of Cas9 - the protein that binds and cuts DNA - to minimize the chance that CRISPR-Cas9 will edit DNA at the wrong place, a key consideration when doing gene therapy in humans. One strategy to achieve improved accuracy is to create mutations in the governing protein domain, called REC3, and see which ones improve accuracy without impacting the efficiency of on-target cutting. "We have found that even minor alterations in the REC3 domain of Cas9 affect the differential between on- and off-target editing, which suggests that this domain is an obvious candidate for in-depth mutagenesis to improve targeting specificity. As an extension of this work, one could perform a more unbiased mutagenesis within REC3 than the targeted mutations we have made," said co-first author Janice Chen, a graduate student in the lab of Dr. Jennifer Doudna, who co-invented the CRISPR-Cas9 gene-editing tool. Co-first authors Chen, Yavuz Dagdas, and Benjamin Kleinstiver, and their colleagues at UC Berkeley, Massachusetts General Hospital, and Harvard University reported their results online on September 20, 2017 in Nature. The article is titled “Enhanced Proofreading Governs CRISPR–Cas9 Targeting Accuracy.” Since 2012, when Dr.

September 19th

PureTech Health Exclusively Licenses Novel Milk-Derived Exosome Technology for Oral Administration of Biologics, Nucleic Acids, and Complex Small Molecules

On September 19, 2017, PureTech Health plc (“PureTech Health” or the “Company”, LSE: PRTC), an advanced, clinical-stage biopharmaceutical company, announced an exclusive licensing agreement with 3P Biotechnologies, Inc., via University of Louisville, for an exosome-based technology (Calix) for the oral administration of biologics, nucleic acids, and complex small molecules. The Calix technology is based on the pioneering research of Ramesh Gupta, PhD, Founder of 3P Biotechnologies, Agnes Brown Duggan Chair in Oncological Research at the James Graham Brown Cancer Center, and Professor in the Department of Pharmacology and Toxicology at University of Louisville. This license, together with additional PureTech Health-generated intellectual property, establishes the company as a leader in the application of milk exosomes for the oral administration of therapeutic molecules. Exosomes, which can contain mixtures of lipids, proteins and nucleic acids, play a critical physiologic role in intercellular communication and the transport of macromolecules between cells and tissues. Mammalian-derived exosomes have attractive potential as vehicles for the administration of a variety of drug payloads, especially nucleic acids, because their natural composition will likely provide superior tolerability over the variety of synthetic polymers currently in use. Previously, exosomes had not been considered viable as vehicles for oral administration of drugs due to their lack of stability under the harsh physiologic conditions associated with transit through the stomach and small intestine. However, the milk-derived exosomes that form the basis for the Calix technology have evolved specifically to accomplish the task of oral transport of complex biological molecules.

Acoustic Microfluidic Device Can Gently and Rapidly Isolate Exosomes from Blood; Isolated Exosomes Can Be Analyzed for Molecular Signatures of Cancer and Other Diseases

Cells secrete nanoscale membraned packets called exosomes that can carry important messages from one part of the body to another. Scientists from MIT and other institutions have now devised a way to intercept these messages, which could be used to diagnose problems such as cancer or fetal abnormalities. Their new device uses a combination of microfluidics and sound waves to isolate these exosomes from blood. The researchers hope to incorporate this technology into a portable device that could analyze patient blood samples for rapid diagnosis, without involving the cumbersome and time-consuming ultracentrifugation method commonly used today. “These exosomes often contain specific molecules that are a signature of certain abnormalities. If you isolate them from blood, you can do biological analysis and see what they reveal,” says Dr. Ming Dao, a principal research scientist in MIT’s Department of Materials Science and Engineering and a senior author of the study, which appears in PNAS the week of September 18, 2017. The paper’s senior authors also include Dr. Subra Suresh, President-Designate of Nanyang Technological University in Singapore, MIT’s Vannevar Bush Professor of Engineering Emeritus, and a former Dean of Engineering at MIT; Dr. Tony Jun Huang, a Professor of Mechanical Engineering and Materials Science at Duke University; and Dr. Yoel Sadovsky, Director of the Magee-Women’s Research Institutein Pittsburgh. The paper’s lead author is Duke graduate student Mengxi Wu. The article is titled “Isolation of Exosomes from Whole Blood by Integrating Acoustics and Microfluidics. In 2014, the same team of researchers first reported that they could separate cells by exposing them to sound waves as they flowed through a tiny channel.

Rutgers Researchers Shed Light on Role of Key Fat-Regulating Enzyme in Human Health; Findings May Hold Clues to Obesity, Diabetes, Cancer, And Other Diseases

had already been known that the enzyme known as phosphatidic acid phosphatase plays a crucial role in regulating the amount of fat in the human body. Controlling it is therefore of interest in the fight against obesity. But scientists at Rutgers University-New Brunswick have now found that getting rid of the enzyme entirely can increase the risk of cancer, inflammation, and other ills. Their findings were published online on July 3, 2017 in the Journal of Biological Chemistry. "The goal of our lab is to understand how we can tweak and control this enzyme," said Dr. George M. Carman, Board of Governors Professor in the Department of Food Science in the School of Environmental and Biological Sciences. "For years, we have been trying to find out how to fine-tune the enzyme's activity so it's not too active, and creating too much fat, but it's active enough to keep the body healthy." The JBC article is titled “Yeast PAH1-Encoded Phosphatidate Phosphatase Controls The Expression of CHO1-Encoded Phosphatidylserine Synthase for Membrane Phospholipid Synthesis.” The enzyme was discovered in 1957 and Gil-Soo Han, Research Assistant Professor in the Rutgers Center for Lipid Research, discovered the gene encoding the enzyme in 2006. The enzyme determines whether the body's phosphatidic acid will be used to create storage fat, or to create the lipids in cell membranes. The current study used baker's yeast as a model organism, becausee it also contains the key enzyme. Dr. Han, study lead author, deleted a gene in yeast to eliminate the enzyme. That led to accumulations of phosphatidic acid, with cells making far more membrane lipids than necessary, said Dr. Carman, who founded the center in Rutgers' New Jersey Institute for Food, Nutrition, and Health a decade ago.

September 18th

New Lung Cell Type Identified; Finding May Lead to New, Non-Traditional Approaches to Treating Pneumonia and Chronic Lung Diseases

A recent study has identified a new lung cell type that is implicated in the body's innate immune defense against the bacteria Streptococcus pneumoniae--one of the leading causes of pneumonia worldwide. The findings, which were published online on September 18, 2017 in the Journal of Clinical Investigation, may lead to new, non-traditional approaches in the fight against pneumonia and chronic lung diseases. The article is titled “Expression of Piwi Protein MIWI2 Defines a Distinct Population of Multiciliated cells.” There are two classifications of cells in the human body: germ cells that are used to make sperm and eggs and somatic cells that make up every other cell in the body including lung cells. There are widespread differences between germ cells and somatic cells underscoring their markedly different roles in human biology. It was previously thought that the MIWI2 gene was only expressed in male germ cells as part of a family of genes that ensure the proper development of sperm. However, researchers at Boston University School of Medicine (BUSM) have discovered that, not only is the same gene expressed in somatic cells in the body, but it also marks a distinct population of multi-ciliated cells that line the upper airways of the lung. "These ciliated cells have hair-like projections that function to sweep mucus and other foreign material out of the lung. However, what sets this new population of ciliated cells apart is that they express the MIWI2 protein and in this report, were found to have a specialized role in controlling lung infection," explains corresponding author Matthew Jones, PhD, Assistant Professor of Medicine at BUSM.

BOOK REVIEW—"Ebola: The Natural and Human History of a Deadly Virus”

The objective of David Quammen’s book, “Ebola: The Natural and Human History of a Deadly Virus” (published October 20, 2014) is stated clearly in the introduction section as “to place the 2014 West Africa outbreak […] within a broader context that makes sense of those mysteries and their partial solutions. My offering here is merely a partial view of the history and science of Ebola” (Quammen, p. 2). Quammen then continues to explain that he did not have a traumatizing experience of losing his loved ones as many have, but did travel through “Ebola habitat” and became very close friends with two men who experienced the horrible realities of the Ebola virus. Quammen uses anecdotes to educate his readers regarding the Ebola virus and similar viruses, such as the Marburg virus for example. In the beginning of the book, Quammen tells about the outbreak in the village of Mayibout 2 in Gabon, Africa, where 18 people mysteriously acquired an illness and quickly died. The original victim had eaten a chimpanzee that was found dead and rotting in the forest, and was then prepared traditionally to eat. Because chimps suffer from the virus and die quickly, as do humans infected with Ebola virus, neither we nor the chimps are the reservoir host. Finding the reservoir host is a great interest of many scientists and public health officials around the world. Another strategy Quammen used to explain the Ebola virus outbreak was comparing it with outbreaks of the Marburg virus, which causes a very similar disease that was recognized about nine years before Ebola. Both viruses are filamentous, lethal RNA viruses and appeared “twisty” to scientists in the labs. Ebola virus had many outbreaks throughout the years starting in 1976. Many research experiments were conducted, most of which were unsuccessful, attempting to isolate the Ebola virus.

Dogs’ Social Skills Linked to Oxytocin Sensitivity

The tendency of dogs to seek contact with their owners is associated with genetic variations in sensitivity for the hormone oxytocin, according to a new study from Linköping University, Sweden. The results have been published in Hormones and Behavior and contribute to our knowledge of how dogs have changed during their development from wolf to household pet. The article is titled “Intranasal Oxytocin and a Polymorphism in the Oxytocin Receptor Gene Are Associated with Human-Directed Social Behavior in Golden Retriever Dogs.” During their domestication from their wild ancestor the wolf to the pets we have today, dogs have developed a unique ability to work together with humans. One aspect of this is their willingness to “ask for help” when faced with a problem that seems to be too difficult. There are, however, large differences between breeds, and between dogs of the same breed. A research group in Linköping, led by Professor Per Jensen, has discovered a possible explanation of why dogs differ in their willingness to collaborate with humans. The researchers suspected that the hormone oxytocin was involved. It is well-known that oxytocin plays a role in social relationships between individuals, in both humans and animals. The effect of oxytocin depends on the function of the structure that it binds to, the receptor, in the cell. Previous studies have suggested, among other things, that differences in dogs’ ability to communicate are associated with variations in the genetic material located close to the gene that codes for the oxytocin receptor. The researchers in the present study examined 60 golden retrievers as they attempted to solve a previously insoluble problem. “The first step was to teach the dogs to open a lid, and in this way, get hold of a treat.

September 15th

Aethlon Medical Is Awarded $300K NCI Government Contract to Develop Device Strategy for Isolating Oncosomes and Non-Malignant Exosomes

Aethlon Medical, Inc. (Nasdaq: AEMD), a therapeutic technology company focused on unmet needs in global health and biodefense, announced, on September 14, 2017, that the National Cancer Institute (NCI) has awarded the Company a government contract (number HHSN261201700022C). The title of this SBIR Topic 359 Phase I contract is "Device Strategy for Selective Isolation of Oncosomes and Non-Malignant Exosomes." The NCI Phase I contract period runs from September 15, 2017 and runs through June 14, 2018. The total amount of the firm fixed price contract is $299,250. The contract calls for two subcontractors to work with the Company. The subcontractors under Aethlon Medical on the contract are University of Pittsburgh and Massachusetts General Hospital. Aethlon Medical is investigating the potential use of the Aethlon Hemopurifier® to reduce the presence of circulating tumor-derived exosomes (oncosomes), which contribute to cancer progression. The Hemopurifier® is currently being advanced to treat life-threatening viral infections under an FDA designated Expedited Access Pathway (EAP) program. The Company is also engaged in the advancement of exosomal biomarkers to diagnose and monitor cancer and other disease conditions. Aethlon Medical is focused on addressing unmet needs in global health and biodefense. The Aethlon Hemopurifier® was designed to reduce the presence of life-threatening viral pathogens from the circulatory system of infected individuals. The technology provides a first-line candidate defense against viruses that are not addressed with approved therapies, including a broad-spectrum of naturally occurring pandemic threats and agents of bioterrorism.