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Scientists ID Signaling Pathway Key to Angiogenesis; Pathway Is Critical for Generating Lumen of New Vessels; Work May Lead to Improvements in Treatment of Ischemia Found in Atherosclerosis and Diabetes

A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies a signaling pathway that is essential for angiogenesis, the growth of new blood vessels from pre-existing vessels. The findings, published online on November 23, 2017 in Nature Communications, may improve current strategies to improve blood flow in ischemic tissue, such as that found in atherosclerosis and peripheral vascular disease associated with diabetes. The open-access article is titled “R-Ras-Akt axis induces endothelial lumenogenesis and regulates the patency of regenerating vasculature.” "Our research shows that the formation of fully functional blood vessels requires activation of protein kinase Akt by a protein called R-Ras, and this mechanism is necessary for the formation of the hallow structure, or lumen, of a blood vessel." says Masanobu Komatsu (photo), PhD, Associate Professor at SBP's Lake Nona campus. "The findings are important because they shed new light on the biological process needed to increase blood flow in ischemic tissues." Previous efforts to treat ischemia by creating new blood vessels have focused on delivering angiogenic growth factors like vascular endothelial growth factor (VEGF) to ischemic sites. But all of these studies, including more than 25 phase II and III clinical trials, have failed to offer significant benefit to patients. Dr. Komatsu's research team used a combination of 3D cell culture and living tissue to show that VEGF promotes vascularization, but the vessel structures formed are chaotic, unstable and non-functional. "Functional vessels need to have a lumen, a pipe-like opening that allows oxygenated blood and nutrients to travel through the body," explains Dr. Komatsu, "and VEGF alone cannot fully support the formation of such a vessel structure."

Codiak Biosciences Receives $76.5 Million More in Funding; Total Funding Exosome Company Has Received Now Totals $168.5 Million

On November 29, 2017, Codiak BioSciences, Inc., a leading exosome therapeutics company, announced the closing of a Series C financing round of $76.5 million. In its two years as a company Codiak's funding totals $168.5 million. Codiak's initial investors, including ARCH Venture Partners, Flagship Pioneering, Fidelity Management and Research Company, the Alaska Permanent Fund, and Alexandria Venture Investments, participated in the Series C round, and were joined by new investors, including Qatar Investment Authority, Boxer Capital of the Tavistock Group, Sirona Capital, EcoR1 Capital, and Casdin Capital. Codiak intends to use the proceeds of the Series C financing to advance its initial product candidates into clinical trials, and to continue to develop the company's transformational exosome therapeutic platform. "Investors are clearly seeing the versatility of exosomes as a therapeutic platform with broad utility and the capacity to address currently undruggable targets, offering multiple paths to clinical and commercial success," said Doug Williams, Ph.D., president and CEO. "Codiak has created a proprietary platform for exosome design and manufacturing that allows for precise targeting of important molecular pathways involved with human disease." Exosomes are nanometer-sized membrane sacs, or vesicles, that are released and received by nearly all cells. Exosomes are an ancient system of intercellular communication, through which they deliver various molecules (DNA, RNA, proteins, lipids) from cell to cell. Upon delivery, exosomal cargo can change biological functions in recipient cells according to the instructions encoded by the payload.

Researchers Devise Improved Gene-Editing Process for Duchenne Muscular Dystrophy

Regenerative medicine researchers at the University of Texas (UT) Southwestern Medical Center have developed an improved and simplified gene-editing technique using CRISPR/Cas9 tools to correct a common mutation that causes Duchenne muscular dystrophy. When researchers used the new single-cut technique on a new mouse model, which they also developed to better study the disease, the mice showed improved muscle quality and strength, the scientists report in Science Translational Medicine. The article is titled “Single-Cut Genome Editing Restores Dystrophin Expression in a New Mouse Model of Muscular Dystrophy.” “We think these advancements will be valuable for the field and can help us move closer to tackling this disease in humans,” said Dr. Eric Olson (photo), Director of the Hamon Center for Regenerative Science and Medicine and Co-Director of the Wellstone Muscular Dystrophy Cooperative Research Center at UT Southwestern. The new approach restored up to 90 percent of dystrophin protein expression throughout the skeletal muscles and the heart in the mouse model. The lack of dystrophin protein is what leads to muscle and heart failure, and eventually premature death, from Duchenne muscular dystrophy (DMD). UT Southwestern researchers are now using the improved technique in human DMD cells and expect they will ultimately be able to correct between 60 and 80 percent of human DMD mutations, said Dr. Olson, also Chairman of Molecular Biology at UT Southwestern. The newly created mouse model, which mimics a gene mutation commonly found in Duchenne muscular dystrophy patients, will be made available to others doing research in this area, said Dr. Olson. It can replace the commonly used version that is decades-old and unlike most of the DNA mutations that cause muscular dystrophy in humans.

Molecular Profiling of Melanoma Tumors Explains Survival Differences After Adoptive T-Cell Therapy

The more times metastasized melanoma has mutated and the patient's immune system has been activated against the tumor, the better the chances of survival after immunotherapy. This is what has emerged from a research collaboration between Lund University in Sweden and Herlev University Hospital in Denmark. The findings were published online on November 23, 2017 in Nature Communications. The open-access article is titled “Mutational and Putative Neoantigen Load Predict Clinical Benefit of Adoptive T Cell Therapy in Melanoma.” Using the body's own immune system to combat tumors, an approach known as immunotherapy, has brought a major breakthrough in cancer care. Whereas we previously had no treatments able to increase survival for certain cancer diagnoses, it is now possible to treat advanced melanoma, for example. One such immunotherapy method currently under clinical trial on patients with advanced melanoma is adoptive T-cell therapy (ACT). The treatment is demanding, both in terms of resources and for the patient, who needs to be in a condition to withstand it. In simple terms, the treatment entails first removing the patient's own T-cells from the tumor. The patient's T-cells are then cultured in the lab and subsequently injected back into the patient. "The aim is for them to seek out and fight the tumor and the circulating tumor cells", explains Dr. Göran Jönsson (photo), researcher at Lund University. He is collaborating with Herlev University Hospital in Copenhagen, which is one of few hospitals in Europe currently conducting clinical trials of this form of immunotherapy. Although the treatment outcomes are promising, only just below half of patients respond to this immunotherapy.

Migraines Linked to High Sodium Levels in Cerebrospinal Fluid

Migraine sufferers have significantly higher sodium concentrations in their cerebrospinal fluid than people without the condition, according to the first study to use a technique called sodium MRI to look at migraine patients. The findings were presented on November 28, 2017 at the annual meeting of the Radiological Society of North America (RSNA) in Chicago November 26-December 1. Migraine, a type of headache characterized by severe head pain, and sometimes nausea and vomiting, is one of the most common headache disorders, affecting about 18 percent of women and 6 percent of men. Some migraines are accompanied by vision changes or odd sensations in the body known as auras. Diagnosis is challenging, as the characteristics of migraines and the types of attacks vary widely among patients. Consequently, many migraine patients are undiagnosed and untreated. Other patients, in contrast, are treated with medications for migraines even though they suffer from a different type of headache, such as the more common tension variety. "It would be helpful to have a diagnostic tool supporting or even diagnosing migraine and differentiating migraine from all other types of headaches," said study author Melissa Meyer, MD, Radiology Resident at the Institute of Clinical Radiology and Nuclear Medicine, University Hospital Mannheim and Heidelberg University in Heidelberg, Germany. Dr. Meyer and colleagues explored a magnetic resonance technique called cerebral sodium MRI as a possible means to help in the diagnosis and understanding of migraines. While MRI most often relies on protons to generate an image, sodium can be visualized as well. Research has shown that sodium plays an important role in brain chemistry.

Critical Link Between Obesity and Diabetes Identified; Antibodies Block Passage of Insulin Through Inner Lining of Blood Vessels & Prevent Insulin from Reaching Muscle Cells

University of Texas (UT) Southwestern researchers have identified a major mechanism by which obesity causes type 2 diabetes, which is a common complication of being overweight that afflicts more than 30 million Americans and over 400 million people worldwide. Researchers found that in obesity, insulin released into the blood by the pancreas is unable to pass through the cells that form the inner lining of blood vessels. As a result, insulin is not delivered to the muscles, where it usually stimulates most of the body's glucose to be metabolized. Blood glucose levels rise, leading to diabetes and its related cardiovascular, kidney, and vision problems, said Dr. Philip Shaul (photo), Director of the Center for Pulmonary and Vascular Biology in the Department of Pediatrics at UT Southwestern. "It was totally unpredicted that a major problem in obesity is the delivery of circulating insulin to your muscle. It was even more surprising that this problem involves immunoglobulins, which are the proteins that make up circulating antibodies," said Dr. Chieko Mineo (photo), Associate Professor of Pediatrics, who is a co-senior author on the report with Dr. Shaul. The researchers found that obese mice have an unexpected chemical change in their immunoglobulins. "The abnormal immunoglobulins then act on cells lining blood vessels to inhibit an enzyme needed to transfer insulin from the bloodstream into the muscle," said Dr. Shaul. "Type 2 diabetes patients have the same chemical change, and if we give a mouse immunoglobulins from a type 2 diabetic individual, the mouse becomes diabetic."

Expression of Certain Genes May Be Key to More Youthful Looking Skin; Specific Gene Expression Patterns Identified

Some individuals’ skin appears more youthful than their chronologic age. Although many people try to achieve this appearance with creams, lotions, injections, and surgeries, new research published online on November 14, 2017 in the Journal of the American Academy of Dermatology indicates that increased expression of certain genes may be the key to intrinsically younger-looking, and younger-behaving, skin. The JAAD article is titled “Age-Induced and Photoinduced Changes in Gene Expression Profiles in Facial Skin of Caucasian Females Across 6 Decades of Age.” “It’s not just the genes you are born with, but which ones turn on and off over time,” said lead author Alexa B. Kimball, MD, MPH, a dermatologist and President and CEO of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, who conducted research for the study while previously at Massachusetts General Hospital. “We found a wide range of processes in the skin affected by aging, and we discovered specific gene expression patterns in women who appear younger than their chronologic age.” To produce a comprehensive model of aging skin, Dr. Kimball and her colleagues collected and integrated data at the molecular, cellular, and tissue levels from the sun-exposed skin (face and forearm) and sun-protected skin (buttocks) of 158 white women ages 20 to 74 years. As part of the study, the team looked for gene expression patterns common in women who appeared years younger than their chronologic age. The physical appearance of facial skin was captured through digital images and analysis. Skin samples were processed for analysis and saliva samples were collected for genotyping. The analyses revealed progressive changes from the 20s to the 70s in pathways related to oxidative stress, energy metabolism, senescence (aging), and skin barrier.

Trisomy 21 Research Breaks New Ground; Researchers Find That Symptoms Are Caused by Uncontrolled Dysregulation of Proteins in Cells; Non-Chromosome 21 Proteins Also Affected

Down's syndrome, also known as trisomy 21, is one of the most common genetic diseases. Researchers from the University of Geneva (UNIGE) and ETH Zurich (ETHZ) in Switzerland have recently analyzed the proteins of individuals with trisomy 21 for the first time: the goal was to improve our understanding of how a supernumerary copy of chromosome 21 can affect human development. Published online on October 31, 2017 in Nature Communications, the research shows that trisomy 21, far from only affecting the proteins encoded by the chromosome 21 genes, also impacts proteins encoded by genes located on other chromosomes. In fact, the cells are overwhelmed by the protein surplus generated by the triplicated genes, and cannot regulate the amount of proteins. These results provide new insight into Down's syndrome and its symptoms based on the study of proteins, revealing the different outcomes of an excess of chromosome 21 on cell behavior. The symptoms of Down's syndrome include facial dysmorphism, intellectual impairment, poor muscular tone, and congenital heart disease. The syndrome results from the presence of three chromosomes 21, which explains why research until now has focused on analyzing DNA and the transcriptome (all the messenger RNAs synthesized from genes of our genome). "Nevertheless," explains Dr. Stylianos E. Antonarakis, Honorary Professor in UNIGE's Faculty of Medicine, "the proteins are highly informative molecules because they are more closely linked to the clinical signs of the syndrome.

Pollinators Use Multiple Cues to Identify Flowers Across Continents

Although at least 75% of our crop species depend on the activities of wild pollinators, little is known about their flower preferences. As global populations of domestic bee pollinators decline, it is of utmost importance for us to understand what factors attract wild pollinators such as hoverflies to flowers, and how these preferences differ in the face of environmental change. Now, a team of scientists from Uppsala University in Sweden and Flinders University in Australia, and the National Centre for Biological Sciences (NCBS) in India have discovered that hoverflies, a group of generalist pollinators, use a combination of cues such as color, shape, and scent to identify flowers. You and I live in a sensory world--sight, sound, touch, and taste blend to give us a sense of our surroundings. However, imagine perceiving the world as a fly, with a brain the size of a pinhead. Yet many insects with miniscule brains manage to do exactly what we do--identify objects like a flower, or a plant. Dr. Karin Nordström's group from the University of Uppsala, Sweden, and Flinders University, Australia, and Dr. Shannon Olsson's team from the NCBS in Bangalore, India, have long been interested in how insects, with their "teeny-tiny" brains can recognize objects such as flowers. Now, through their collaborative work on hoverflies, the two teams have found an answer. These insects use a multimodal sensory mechanism--in other words, hoverflies require a combination of clues including shape, size, color, and scent--to recognize flowers in different environments across the world. The teams' results are especially important with respect to our scarce knowledge of what attracts wild insect pollinators to flowers. Although at least 75% of our crop species depend on the activities of wild pollinators, little is known about their flower preferences.

Blocking Sensory Neuron Release of Exosomes Containing MicroRNA-21 May Help Reduce Neuropathic Pain

New research from King’s College London has revealed a previously undiscovered mechanism of cellular communication, between neurons and immune cells, in neuropathic pain. The authors, who published their findings online on November 24, 2017 in Nature Communications, identified a new method of treating neuropathic pain in mice, which could be more safe and effective than current treatments consisting of opioids and antiepileptic drugs. The open-access article is titled “Exosomal Cargo Including MicroRNA Regulates Sensory Neuron To Macrophage Communication After Nerve Trauma.” Neuropathic pain is a type of chronic pain that is usually caused by an injury to nerves, but the pain persists long after the injury has healed. Neuropathic pain may occur after surgery or a car accident, or in some cases when a limb has been amputated. Currently, the only available drugs for neuropathic pain are either opioids or antiepileptic medication. Opioids, like morphine and tramadol, are highly addictive and the National Health Service (England, Scotland, Wales) have recently raised concerns about prescription of these drugs, due to opioid overdoses more than doubling in the last decade. In the US, an opioid “epidemic” has recently been declared due to the rising number of deaths linked to these drugs. In contrast, antiepileptic medication is not addictive but is often accompanied by a whole host of unpleasant side effects such as dizziness, fatigue, nausea, and weight gain. However, people with neuropathic pain have very little choice when it comes to other treatment options because the cause of neuropathic pain is so poorly understood.

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