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Animal Study Reveals That Secretions (Extracellular Vesicles) from Cardiosphere-Derived Cells Could “Turn Back the Clock” for Age-Related Heart Conditions

Cardiac stem cell infusions could someday help reverse the aging process in the human heart, making older ones behave younger, according to a new study from the Cedars-Sinai Heart Institute. "Our previous lab studies and human clinical trials have shown promise in treating heart failure using cardiac stem cell infusions," said Eduardo Marbán, MD, PhD, Director of the Cedars-Sinai Heart Institute and the primary investigator of the study. "Now we find that these specialized stem cells could turn out to reverse problems associated with aging of the heart." The study was published online on August 14, 2017 in the European Heart Journal. The article is titled “Cardiac and Systemic Rejuvenation After Cardiosphere-Derived Cell Therapy in Senescent Rats.” In the study, investigators injected cardiosphere-derived cells, a specific type of stem cell known as CDCs, from newborn laboratory rats into the hearts of rats with an average age of 22 months, which is considered aged. Other laboratory rats from the same age group were assigned to receive placebo treatment, saline injections instead of stem cells. Both groups of aged rats were compared to a group of young rats with an average age of 4 months. Baseline heart function was measured in all rats, using echocardiograms, treadmill stress tests, and blood analysis. The older rats underwent an additional round of testing one month after receiving cardiosphere-derived cells that came from young rats. "The way the cells work to reverse aging is fascinating," Dr. Marbán said. "They secrete tiny vesicles [extracellular vesicles] that are chock-full of signaling molecules such as RNA and proteins. The vesicles from young cells appear to contain all the needed instructions to turn back the clock."

Brain Scan Study Adds to Evidence That Lower Brain Levels of Serotonin Transporters Are Linked to Dementia; Results Suggest Serotonin Loss May Be a Key Player in Cognitive Decline, Not Just a Side-Effect of Alzheimer's Disease

In a study examining brain scans of people with mild loss of thought and memory ability, Johns Hopkins researchers report evidence of lower levels of the serotonin transporter -- a natural brain chemical that regulates mood, sleep, and appetite. Previous studies from Johns Hopkins and other centers have shown that people with Alzheimer's disease and severe cognitive decline have severe loss of serotonin neurons, but the studies did not show whether those reductions were a cause or effect of the disease. Results of the new study of people with very early signs of memory decline, the researchers say, suggest that lower levels of serotonin transporters may be drivers of the disease rather than a byproduct. A report on the study, published in the September 2017 issue of Neurobiology of Disease, also suggests that finding ways to prevent the loss of serotonin or introducing a substitute neurotransmitter could slow or stop the progression of Alzheimer's disease and perhaps other dementias. The article is titled “Molecular Imaging of Serotonin Degeneration in Mild Cognitive Impairment." “Now that we have more evidence that serotonin is a chemical that appears affected early in cognitive decline, we suspect that increasing serotonin function in the brain could prevent memory loss from getting worse and slow disease progression," says Gwenn Smith, PhD, Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine and Director of Geriatric Psychiatry and Neuropsychiatry at Johns Hopkins University School of Medicine. Serotonin levels that are lower and out of balance with other brain chemicals such as dopamine are well known to significantly impact mood, particularly depression, and drugs that block the brain's "reuptake" of serotonin (known as SSRIs) are specific treatments for some major forms of depression and anxiety.

Discovery of New Prostate Cancer Biomarkers Could Improve Precision Therapy; SPOP Mutations Confer Resistance to BET Inhibitors

Mayo Clinic researchers have identified a new cause of treatment resistance in prostate cancer. Their discovery also suggests ways to improve prostate cancer therapy. The findings were published online on August 14, 2017 in Nature Medicine. The article is titled “Prostate Cancer–Associated SPOP Mutations Confer Resistance to BET Inhibitors Through Stabilization of BRD4.” In the publication, the authors explain the role of mutations within the SPOP gene on the development of resistance to one class of drugs. SPOP mutations are the most frequent genetic changes seen in primary prostate cancer. These mutations play a central role in the development of resistance to drugs called BET-inhibitors. BET (bromodomain and extra-terminal domain) inhibitors are drugs that prevent the action of BET proteins. These proteins help guide the abnormal growth of cancer cells. As a therapy, BET-inhibitors are promising, but drug resistance often develops, says Haojie Huang, PhD, senior author and a molecular biologist within Mayo Clinic's Center for Biomedical Discovery. Prostate cancer is among the most frequently diagnosed malignancies in the United States. It is also the third leading cause of cancer death in American men, according to the American Cancer Society. Because of this, says Dr. Huang, improving treatments for prostate cancer is an important public health goal. In the publication, the authors report SPOP mutations stabilize BET proteins against the action of BET-inhibitors. By this action, the mutations also promote cancer cell proliferation, invasion, and survival.

Blood Biopsy Test Reads Platelet-Associated Tumor RNA to Detect Human Lung Cancer; Algorithm Models Swarming Behavior of Birds, Insects, & Fish

Researchers in the Netherlands have designed a different approach to the liquid biopsy. Rather than looking for evidence of cancer DNA or other biomarkers in the blood, their test (called thromboSeq) could diagnose non-small cell lung cancer with close to 90% accuracy by detecting tumor RNA absorbed by circulating platelets, also known as thrombocytes. Non-small cell lung cancers make up the majority of lung cancer cases. The research was published in the August 14, 2017 issue of Cancer Cell. The open-access article is titled “Swarm Intelligence-Enhanced Detection of Non-Small Cell Lung Cancer Using Tumor-Educated Platelets." "Ultimately, the aim of liquid biopsy-based cancer detection is to detect all cancers at once in an early stage; an all-in-one test," says first author Dr. Myron Best, a researcher at the Department of Neurosurgery of the VU University Medical Center in Amsterdam and the Cancer Center Amsterdam. "ThromboSeq might not only provide lung cancer diagnostics, but potentially any other tumor type as well, and may enable tumor-type stratification." Platelets are short-lived blood cells known to form blood clots in response to injury. However, platelets also respond to a range of inflammatory events and cancer. Because platelet cells don't have a nucleus of their own, all RNA found in platelets either comes from megakaryocytes (the cells that form platelets in bone marrow) or from RNA the platelets absorbed while circulating in blood. Platelets in a cancer-free person will contain a different compilation of RNA than platelets that interacted with a tumor, known as tumor-educated platelets.

Portable DNA Sequencer (MinION) Enables Researchers to Monitor Evolution of Zika Virus

An international group of researchers on board a mobile laboratory equipped with an innovative hand-held genetic sequencing device are tracking the movement of the Zika virus since it disembarked in Brazil and began spreading through the Americas. According to the scientists, their aim is to monitor the viral genome's evolution and to understand what has happened, so as to be able to predict future outbreaks and to keep diagnostic methods up to date. The first results of Project ZiBRA (Zika in Brazil Real Time Analysis), which is supported by Brazil's Ministry of Health, FAPESP, and several other entities, were published online on May 24, 2017 in Nature. The article is titled “Establishment and Cryptic Transmission of Zika Virus in Brazil and the Americas.” "By combining epidemiological and genetic data, we were able to see that Zika circulated silently in all regions of the Americas at least a year before the virus was first confirmed, in May 2015," said Dr. Nuno Faria, a researcher in the Zoology Department of Oxford University, UK, and first author of the article. According to Dr. Faria, Zika was introduced into Brazil's Northeast region in February 2014. Transmission in the region probably occurred throughout the year but was not especially pronounced. "The major outbreak very probably occurred in 2015, concurrently with the dengue outbreak," he said. "Zika spread from Northeast to Southeast Brazil [initially Rio de Janeiro] and also to the Caribbean and other countries in South and Central America, eventually reaching Florida." The findings were based on an analysis of 254 whole genomes of the pathogen, 54 of them sequenced in this study. Most of the new genetic data were obtained using MinION, a palm-sized sequencer made by Oxford Nanopore Technologies and weighing less than 100 g.

RoosterBio and Exopharm Partner to Bring High-Grade Therapeutic Extracellular Vesicles/Exosomes into Clinical Practice

On August 7, 2017, RoosterBio, Inc. and Exopharm Pty Ltd announced a formal heads of agreement under which they will work together on a Stem Cell Exomere Program, aimed at bringing high-grade therapeutic extracellular vesicles/exosomes derived from adult stem cells into clinical practice. Exosomes secreted by stem cells are a new class of therapeutic product well suited to be used in regenerative medicine (“RM”) applications, but large-scale stem cell manufacturing bottlenecks impede broad clinical use of these natural bioactive nanoparticles. RoosterBio, based in Frederick, Maryland, USA, has strengths in human mesenchymal stem/stromal cells (hMSC) technology-based process and product design innovation, and develops commercially-viable biomanufacturing processes that support both upstream processing (USP) and downstream processing (DSP), offered as “acceleration services” to customers. Exopharm is a Melbourne, Australia-based biotechnology company specializing in its patent-applied-for LEAP isolation technology, Exomere manufacturing and clinical development, and commercialization of its Exomere technology. Exomeres are a pharma-grade fraction of cell-derived bilayer lipid membrane extracellular vesicles in a size range of around 40-200 nm purified using Exopharm’s LEAP ligand technology. Recent small-scale human studies have demonstrated that purified extracellular vesicles/exosomes derived from adult stem cells are safe and effective – yet there is no accepted and standardized commercial-scale manufacturing process for these submicroscopic particles. RoosterBio and Exopharm have complementary technologies, competencies, and commercial objectives – were proud to announce the establishment of their joint Stem Cell Exomere Program.

BMAL1 Protein in Muscle, Not Brain, Regulates Sleep in Mice

Scientists exploring the brain for answers to certain sleep disorders may have been looking in the wrong place. A new study shows that a protein in muscle can lessen the effects of sleep loss in mice, a surprising revelation that challenges the widely accepted notion that the brain controls all aspects of sleep. The new finding – the result of a collaboration between the University of Texas (UT) Southwestern’s Peter O’Donnell Jr. Brain Institute and two other medical centers – gives scientists a new target besides the brain to develop therapies for people with excessive sleepiness. “This finding is completely unexpected and changes the ways we think sleep is controlled,” said Dr. Joseph S. Takahashi (photo), Chairman of Neuroscience at UT Southwestern Medical Center and Investigator with the Howard Hughes Medical Institute. The research published online on July 20, 2017 in eLife demonstrates how a circadian clock protein (BMAL1) in the muscle regulates the length and manner of sleep. The article is titled “Bmal1 function in skeletal muscle regulates sleep.” While the protein’s presence or absence in the brain had little effect on sleep recovery, mice with higher levels of BMAL1 in their muscles recovered from sleep deprivation more quickly. In addition, removing BMAL1 from the muscle severely disrupted normal sleep, leading to an increased need for sleep, deeper sleep, and a reduced ability to recover. Dr. Takahashi said the finding may eventually lead to therapies that could benefit people in occupations requiring long stretches of wakefulness, from military to airline piloting. “These studies show that factors in muscles can signal to the brain to influence sleep. If similar pathways exist in people, this would provide new drug targets for the treatment of sleep disorders,” said Dr.

Yale Scientists Reveal Role for Lysosome Transport in Alzheimer's Disease Progression; Finding Suggests Possible New Therapeutic Approaches

Researchers from the Yale University School of Medicine have discovered that defects in the transport of lysosomes within neurons promote the buildup of protein aggregates in the brains of mice with Alzheimer's disease. The study, which was published on August 7, 201 in The Journal of Cell Biology (JCB), suggests that developing ways to restore lysosome transport could represent a new therapeutic approach to treating the neurodegenerative disorder. The open-access article is titled “Impaired JIP3-Dependent Axonal Lysosome Transport Promotes Amyloid Plaque Pathology.” Alzheimer's disease is the sixth leading cause of death in the United States, with over 5 million Americans currently estimated to be living with the disorder. A characteristic feature of the disease is the formation of amyloid plaques inside the brain. The plaques consist of extracellular aggregates of a toxic protein fragment called β-amyloid surrounded by numerous swollen axons, the parts of neurons that conduct electric impulses to other nerve cells. These axonal swellings are packed with lysosomes, cellular garbage disposal units that degrade old or damaged components of the cell. In neurons, lysosomes are thought to "mature" as they are transported from the ends of axons to the neuronal cell body, gradually acquiring the ability to degrade their cargo. The lysosomes that get stuck and accumulate inside the axonal swellings associated with amyloid plaques fail to properly mature, but how these lysosomes contribute to the development of Alzheimer's disease is unclear. One possibility is that they promote the buildup of β-amyloid because some of the enzymes that generate β-amyloid by cleaving a protein called amyloid precursor protein (APP) accumulate in the swellings with the immature lysosomes.

Scientists Create Potential Stem Cell Therapy for Lung Fibrosis Conditions, Including Idiopathic Pulmonary Fibrosis (IPF)

A team of scientists from the University of North Carolina (UNC) School of Medicine and North Carolina State University (NCSU) has developed promising research towards a possible stem cell treatment for several lung conditions, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cystic fibrosis -- often-fatal conditions that affect tens of millions of Americans. In the journal Respiratory Research, the scientists demonstrated that they could harvest lung stem cells from people using a relatively non-invasive, doctor's-office technique. They were then able to multiply the harvested lung cells in the lab to yield enough cells sufficient for human therapy. Thus open-access article, published online on June 30, 2017, is titled “Derivation of Therapeutic Lung Spheroid Cells from Minimally Invasive Transbronchial Pulmonary Biopsies.” In a second study, published in Stem Cells Translational Medicine, the team showed that in rodents they could use the same type of lung cell to successfully treat a model of IPF - a chronic, irreversible, and ultimately fatal disease characterized by a progressive decline in lung function. The open-access article, published online on August 7, 2017, is titled “Safety and Efficacy of Allogeneic Lung Spheroid Cells in a Mismatched Rat Model of Pulmonary Fibrosis.” The researchers have been in discussions with the FDA and are preparing an application for an initial clinical trial in patients with IPF. "This is the first time anyone has generated potentially therapeutic lung stem cells from minimally invasive biopsy specimens," said co-senior author of both papers Jason Lobo, MD, an Assistant Professor of Medicine at UNC and Medical Director of Lung Transplant and Interstitial Lung Disease.

Using CRISPR and Skin Grafts, Researchers Boost Insulin Levels to Correct Diet-Induced Obesity and Diabetes in Mice; Gene Therapy Via Skin Could Treat Many Diseases, Scientists Suggest

A research team based at the University of Chicago has overcome challenges that have limited gene therapy and demonstrated how their novel approach with skin transplantation could enable a wide range of gene-based therapies to treat many human diseases. In the August 3, 2017 issue of Cell Stem Cell, the researchers provide "proof-of-concept." They describe a new form of gene-therapy - administered through skin transplants - to treat two related and extremely common human ailments: type-2 diabetes and obesity. "We resolved some technical hurdles and designed a mouse-to-mouse skin transplantation model in animals with intact immune systems," said study author Xiaoyang Wu, PhD, Assistant Professor in the Ben May Department for Cancer Research at the University of Chicago. "We think this platform has the potential to lead to safe and durable gene therapy, in mice and we hope, someday, in humans, using selected and modified cells from skin." Beginning in the 1970s, physicians learned how to harvest skin stem cells from a patient with extensive burn wounds, grow them in the laboratory, then apply the lab-grown tissue to close and protect a patient's wounds. This approach is now standard. However, the application of skin transplants is better developed in humans than in mice. "The mouse system is less mature," Dr. Wu said. "It took us a few years to optimize our 3D skin organoid culture system." This study, entitled "Engineered Epidermal Progenitor Cells Can Correct Diet-Induced Obesity and Diabetes," is the first to show that an engineered skin graft can survive long term in wild-type mice with intact immune systems. "We have a better than 80 percent success rate with skin transplantation," Dr. Wu said. "This is exciting for us." The article is open-access.

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