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Stem Cell Medicine Ltd Licenses Exosome Technology (Exosomes Derived from Adult Stem Cells) for Intranasal Treatment of Autism Spectrum Disorder (ASD) from Tel Aviv University; Pre-Clinical Testing Shows Improvement in Several Behavioral Phenotypes

On January 2, 2019, Stem Cell Medicine Ltd. (SCM), a biotechnology company developing new therapies for neurological indications, including mesenchymal stem cells (MSCs) and anti-BMP (bone morphogenic protein) molecules for the treatment of multiple sclerosis, and gene therapy for the treatment of neuropathic pain, announced that it has licensed an innovative exosomes-based technology for the treatment of neurodegenerative and neuropsychiatric indications, specifically, autism spectrum disorder (ASD). The treatment is based on exosomes, derived from adult stem cells (MSC-exo), that are administered intranasally. The technology was developed by Professor Dani Offen, Sackler School of Medicine, Sagol School of Neurosciences, Tel Aviv University, and was licensed from Ramot, the Business Engagement Center at Tel Aviv University. The first indication to be developed with the exosome technology is ASD, which is a group of neurodevelopmental disorders characterized by three core symptoms: severe impairment of social interactions and communication skills, increased repetitive behaviors, and cognitive inflexibility. The prevalence of ASD has been steadily increasing in children over the past several years, with no effective treatment, hence, it represents a growing unmet medical need. More than 3.5 million Americans live with ASD. According to the US Department of Health and Human Services (CDC), the prevalence of autism in US children in 2018 is estimated to be 1 in 59 children and has increased from 1 in 110 children in 2010, making it the fastest-growing developmental disability with currently no FDA-approved drug. Given the size of the patient population and lack of treatments, the market opportunity is compelling.

Sex Differences in Glioblastoma Brain Tumors Revealed by Analysis of Patient Imaging, Transcriptome, and Survival Data—“We Should Definitely Develop and Evaluate Sex-Specific Treatment Regimens for Glioblastoma,” Research Leader Says

For decades, scientists have recognized that more males get cancer and die of the disease than females. This is true for many types of cancer, including the deadly brain tumor glioblastoma (GBM). Now, a team of researchers led by scientists at the Washington University School of Medicine in St. Louis has identified distinct molecular signatures of glioblastoma in men and women that help explain such underlying disparities in patients’ response to treatment and survival. The research suggests that tailoring treatments to men and women with glioblastoma based on the molecular subtypes of their tumors may improve survival for all patients. The findings were published January 2, 2019 in Science Translational Medicine. The open-access article is titled “Sex Differences in GBM Revealed by Analysis of Patient Imaging, Transcriptome, and Survival Data.” “It is our expectation that this study could have an immediate impact on the care of patients with glioblastoma and further research, as the findings indicate we should be stratifying male and female glioblastoma into risk groups and evaluating the effectiveness of treatment in a sex-specific manner,” said Joshua B. Rubin, MD, PhD, a Washington University Professor of Pediatrics and of Neuroscience and the study’s co-senior author. “The biology of sex differences and its applications in medicine are highly relevant, but almost always ignored aspects of personalized treatments.” Glioblastoma is the most common malignant brain tumor and kills about half of patients within 14 months of diagnosis. It is diagnosed nearly twice as often in males, compared with females. The tumor is most often diagnosed in people over age 50, and standard treatment is aggressive -- surgery, followed by chemotherapy and radiation.

New Findings on Genes Driving Male-Female Brain Differences & Puberty Timing; Scientists ID Genetic Pathway to Sexual Maturation in C. elegans That May Serve Same Function in Humans; Sex Differences in Men’s & Women’s Brains May Be Hard-Wired

Researchers have identified a group of genes that induces differences in the developing brains of male and female roundworms and triggers the initiation of puberty, a genetic pathway that may have the same function in controlling the timing of sexual maturation in humans. The study, led by Columbia University scientists, offers new evidence for direct genetic effects in sex-based differences in neural development and provides a foundation to attempt to understand how men's and women's brains are wired and how they work. The research was published January 1, 2019 in eLife, an open-access journal founded by the Howard Hughes Medical Institute (HHMI), the Max Planck Society, and the Wellcome Trust. The article is titled “Timing Mechanism of Sexually Dimorphic Nervous System Differentiation.” Scientists have long known that puberty is accompanied by substantial changes in the brain characterized by the activation of neurons that produce hormonal signals. But what causes the brain to start releasing the hormones that switch on puberty has remained elusive. "In this paper we show that a pathway of regulatory genes acts within specific neurons to induce anatomical and functional differences in the male versus female brain," said lead study author Oliver Hobert, PhD, Professor in Columbia's Department of Biological Sciences and a HHMI investigator. "Remarkably, we found that each member of this pathway is conserved between worms and humans, indicating that we have perhaps uncovered a general principle for how sexual brain differences in the brain are genetically encoded." For their study, the researchers worked with the transparent roundworm C. elegans, the first multicellular organism to have its genome sequenced.

Why Olfactory Cilia Use Outward-Flowing Cl−, Not Inward-Flowing Na+, to Generate Current; Need for Consistent Response in Variable Environments & Tiny Volume of Cilia Are Key; Findings Relevant to Nerve-Ending Pathology in Neurodegenerative Disease

Imagine trying to figure out how something works when that something takes place in a space smaller than a femtoliter: one quadrillionith of a liter. Now, two scientists with a nose for solving mysteries have used a combination of mathematical modeling, electrophysiology, and computer simulations to explain how cells communicate effectively in highly constricted spaces such as the olfactory cilia, where odor detection takes place. The findings will inform future studies of cellular signaling and communication in the olfactory system and also in other confined spaces of the nervous system. Study co-author Johannes Reisert, PhD, a Monell Chemical Senses Center cell physiologist, comments, "Ion channels and how their currents change ion concentrations inside cells are notoriously difficult to study. Our modeling-based approach enables us to better understand, not only how olfaction works, but also the function of small nerve endings such as dendrites, where pathology is associated with many neurodegenerative diseases." In the study, published online on December 31, 2018 in PNAS, the scientists asked why olfactory receptor cells communicate with the brain using a fundamentally different series of electrical events than used by sensory cells in the visual or auditory systems. The article is titled “Ca2+-Activated Cl− Current Ensures Robust and Reliable Signal Amplification in Vertebrate Olfactory Receptor Neurons.” Olfaction begins when, in a process similar to a key fitting into a lock, an airborne chemical molecule travels through the nasal mucus to bind with an olfactory receptor embedded on the wall of a nerve cell within the nose. The olfactory receptors are located on cilia, elongated super-thin threadlike structures less than 0.000004 inches in diameter, which extend from the nerve cell into the mucus.

Chemotherapy Can Stimulate Release of Metastasis-Promoting Exosomes from Breast Cancer Cells; The Exosomes Release Their Contents in the Lungs; Monocyte Inhibitors May Block This Chemotherapy/Exosome-Associated Metastasis

Some patients with breast cancer receive chemotherapy before the tumor is removed with surgery. This approach, called “neoadjuvant” therapy, helps to reduce the size of the tumor to facilitate breast-conserving surgery, and can even eradicate the tumor, leaving few or no cancerous cells for the surgeon to remove. In those cases, the patients are very likely to remain cancer-free for life after surgery. But not all tumors shrink under chemotherapy. If the tumor resists neoadjuvant therapy, there can be a higher risk of developing metastatic disease, meaning that the tumor will recur in other organs, such as bones or lungs. This could be due to cancerous cells that resist chemotherapy and spread to other organs while the primary tumor is being treated. Now, an international team of scientists led by Dr. Michele De Palma, PhD, at EPFL (Ecole Polytechnique Fédérale De Lausann) in Switzerland, has shed new light into this process. Working with experimental tumor models, the researchers found that two chemotherapy drugs frequently used for patients, paclitaxel and doxorubicin, induce mammary tumors to release small vesicles called exosomes. Under chemotherapy, the exosomes contain the protein annexin-A6, which is not present in the exosomes released from untreated tumors. "It seems that loading of annexin-A6 into exosomes is significantly enhanced in response to chemotherapy," explains Ioanna Keklikoglou, PhD, first author of the study. After being released from a chemotherapy-treated tumor, the exosomes circulate in the blood. Upon reaching the lung, the exosomes release their content, including annexin-A6. This stimulates the lung cells to release another protein, CCL2, which attracts immune cells called monocytes.

A Healing Bit of the Old Sod—Ancient Irish Soil Long Reputed to Have Healing Powers Found to Contain Bacterium Strain Effective Against Multiple Antibiotic-Resistant Superbugs; "Answer to Very Modern Problem May Lie in Wisdom of the Past"

Researchers analyzing soil from Ireland long thought to have medicinal properties have discovered that it contains a previously unknown strain of bacteria which is effective against four of the top six superbugs that are resistant to antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA). Antibiotic-resistant superbugs could kill up to 1.3 million people in Europe by 2050, according to recent research. The World Health Organization (WHO) describes the problem as "one of the biggest threats to global health, food security, and development today.” The new strain of bacteria was discovered by a team based at Swansea University Medical School in Wales, and made up of researchers from Wales, Brazil, Iraq, and Northern Ireland. They have named the new strain Streptomyces sp. myrophorea. The soil they analyzed originated from an area of County Fermanagh, Northern Ireland, which is known as the Boho Highlands (photo shows limestone grassland in foreground of the Boho Highlands). It is an area of alkaline grassland (S. myrophorea can grow at pH’s as high as 10.5 and is highly resistant to intense gamma radiation) and the soil is reputed to have healing properties. The search for replacement antibiotics to combat multi-resistance has prompted researchers to explore new sources, including folk medicines: a field of study known as ethnopharmacology. They are also focusing on environments where well-known antibiotic producers like Streptomyces can be found. One of the research team, Dr. Gerry Quinn, a previous resident of Boho, County Fermanagh, had been aware of the healing traditions of the area for many years. Traditionally, a small amount of soil was wrapped up in cotton cloth and used to heal many ailments including toothache, and throat and neck infections.

Scientists Pinpoint Specific DNA Sequences That Regulate Chromatin Structure & Replication Timing

A team of Florida State University (FSU) researchers, together with colleagues from other institutions, has unlocked a decades-old mystery about how a critical cellular process is regulated and what that could mean for the future study of genetics. In cells, DNA and its associated material replicate at regular intervals, a process essential to all living organisms. This contributes to everything from how the body responds to disease to hair color. DNA replication was identified in the late 1950s, but since then researchers across the globe have come up short trying to understand exactly how this process was regulated. Now, they believe they know. FSU’s David Gilbert, PhD, the J. Herbert Taylor Distinguished Professor of Molecular Biology, and doctoral student Jiao Sima are the senior and first authors, respectively, on a report published online on December 27, 2018 in Cell that showed there are specific points along the DNA molecule that control replication. The article is titled “Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication.” "It's been quite a mystery," Dr. Gilbert said. "Replication seemed resilient to everything we tried to do to perturb it. We've described it in detail, shown it changes in different cell types and that it is disrupted in disease. But until now, we couldn't find that final piece, the control elements or the DNA sequences that control it." Notably, Dr. Gilbert's professorship is in honor of a former FSU professor named J. Herbert Taylor. In the late 1950s, Professor Taylor demonstrated how different segments of chromosomes duplicate and published more than 100 papers on chromosome structure and replication. Roughly 60 years later, Dr. Gilbert determined how replication was regulated.

Neurite Shrinking in Aging Mice Is Related to Mitochondria Dysfunction Caused by Problems with Protein Supply Chain at Ends of Neurites; Huntington’s Disease Protein Interferes with Same Supply Chain and Causes HD-Similar Disease in Mice

To test the hunch, Dr. Friedlander's team used genetically modified mice that carried a mutant version of the human huntingtin protein. These mice exhibit symptoms of the disease, including accelerated neuronal death. Their findings were similar to what they had seen in the cells, but more pronounced. There were fewer mitochondria at the ends, and what remained was more dysfunctional than in normal neurons. There was also more activation of caspases, and increased levels of cell death. A hallmark of neurodegenerative diseases like Huntington's is the progressive death of nerve cells in the brain. The cells don't die quickly, though. They first start to disconnect from each other because their neurites -- long finger-like extensions that make connections all through the brain -- become smaller. Now, using animal models and nerve cells grown in the lab, researchers from the University of Pittsburgh (Pitt) School of Medicine suggest a new mechanism dubbed "neuritosis" that might explain neurons shrinking in Huntington's and other neurodegenerative diseases, opening new targets for therapy. The study was published online on December 24, 2018 in PNAS. The article is titled “Mitochondria Modulate Programmed Neuritic Retraction.” Neuritosis is a process that hasn't been recognized or described until now and could play a very important role in normal brain development, aging, and neurodegenerative disease," said senior author Robert Friedlander, MD, Chair and Walter E. Dandy Professor of Neurosurgery and Neurobiology at Pitt's School of Medicine. It all started when Sergei Baranov, PhD, a staff scientist in Dr. Friedlander's lab, noticed an interesting phenomenon in mouse nerve cells that he was growing in the lab. "Their mitochondria, the cellular powerhouses, weren't working as well at the neurite ends" said Dr. Baranov.

Support for Exaggerated Immune Response As Possible Trigger for Chronic Fatigue Syndrome

New research from King’s College London finds that an exaggerated immune response can trigger long-lasting fatigue, potentially explaining how chronic fatigue syndrome (CFS) begins. The study is the most in-depth biological investigation yet into the role of the immune system in lasting symptoms of fatigue. CFS, also known as myalgic encephalomyelitis (ME), is a long-term illness which is characterized by extreme tiredness. The underlying biology of CFS has remained a mystery, hampering the search for treatments. There is some evidence that the immune system plays a role in triggering CFS and many patients report their illness starting with a challenge to the immune system such as a viral illness. By the time patients are diagnosed, it is too late to catch CFS in its earliest stages, and it is impossible to assess the biology of patients before the illness develops. To get around this problem, researchers from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) used a model for CFS based on a treatment for hepatitis C called interferon-alpha. Interferon-alpha activates the immune system in the same way as a powerful infection. A lot of patients develop acute fatigue during treatment with interferon-alpha and a minority go on to have a CFS-like illness, where fatigue lasts for more than six months after the treatment ends. The researchers measured fatigue and immune system markers in 55 patients before, during, and after treatment with interferon-alpha, tracking which people developed the persistent CFS-like illness. The team found differences in the immune systems of 18 patients who developed lasting fatigue compared to those who recovered as normal.

Cholesterol-Lowering Drugs Reduce Brown Fat

A certain proportion of the adult population has not only white adipose (or fatty) tissue (left), but also the brown kind (right). This brown adipose tissue helps to convert sugar and fat into heat. People with brown adipose tissue are better at regulating their body temperature in the winter, and are less likely to suffer from excess weight or diabetes. An international team of researchers led by Dr. Christian Wolfrum, Professor for Translational Nutritional Biology at ETH Zurich, has now discovered that the statin class of pharmaceuticals reduces the formation of brown adipose tissue. The article was published online on December 20,2018 in Cell Metabolism. It is titled “Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation.” Statins are prescribed as a way to reduce the risk of a heart attack because they reduce cholesterol levels in the blood. They are among the most commonly prescribed drugs worldwide. Dr. Wolfrum and his colleagues have been researching brown adipose tissue for many years. They looked into the question of how "bad" white fat cells, which form the layer of fat under our skin, become "good" brown fat cells. Having conducted cell culture experiments, they found out that the biochemical pathway responsible for producing cholesterol plays a central role in this transformation. They also discovered that the key molecule regulating the transformation is the metabolite geranylgeranyl pyrophosphate. Earlier studies showed that the cholesterol biochemical pathway is also central to the functioning of statins; one of their effects is to reduce the production of geranylgeranyl pyrophosphate. This is why the researchers wanted to know whether statins also impact the formation of brown adipose tissue.

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