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Connectome Organization in Childhood Acute Lymohoblastic Leukemia (ALL) and Risk of Delayed Neurodevelopment

A new study provides novel insights into the cognitive effects of childhood acute lymphoblastic leukemia (ALL) and of chemotherapeutic treatment in long-term survivors of ALL. The findings from comparative studies of structural and functional connectome organization, showing that connectome disruption is associated with delayed neurodevelopment, were published online on August 1, 2018 in an article in Brain Connectivity, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. You may click on the following link to read the full-text article free on the Brain Connectivity website through September 27, 2018 (https://www.liebertpub.com/doi/10.1089/brain.2017.0574). (Editor’s Note: A connectome is a comprehensive map of neural connections in the brain, and may be thought of as its "wiring diagram.” More broadly, a connectome would include the mapping of all neural connections within an organism's nervous system.) In the article entitled "Brain Network Connectivity and Executive Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia," Kevin Krull, PhD, St. Jude Children's Research Hospital, Memphis, Tennessee and a team of researchers from St. Jude's and the University of Texas MD Anderson Cancer Center in Houston, Texas, reported poor global connectivity and lower information exchange and network integration in study participants with executive dysfunction - compared to those without - which is one of the most consistently observed deficits observed in this population. The study included 161 long-term survivors of ALL who were 8-21 years of age.

How Cholera Bacterium Survives Aquatic Predators

The cholera-causing bacterium, Vibrio cholerae, is commonly found in aquatic environments, such as oceans, ponds, and rivers. There, the bacterium has evolved formidable skills to ensure its survival, growth, and occasional transmission to humans, especially in endemic areas of the globe. One of the ways the pathogen defends itself against predatory aquatic amoebas involves "hitchhiking" them and hiding inside the amoeba. Once there, the bacterium resists digestion and establishes a replication niche within the host's osmoregulatory organelle. This organelle is essential for the amoeba to balance its internal water pressure with the pressure exerted by the environment. In a new study, the group of Dr. Melanie Blokesch at EPFL (Ecole Polytechnique Fédérale de Lausanne), in collaboration with the BioEM facility headed by Dr. Graham Knott, has deciphered the molecular mechanisms that V. cholerae uses to colonize aquatic amoebas. The study was published online on Aiugust 27, 2018 in Nature Communications. The open-access article is titled “Molecular Insights into Vibrio Cholerae's Intra-Amoebal Host-Pathogen Interactions.” The researchers demonstrated that the pathogen uses specific features that allow it to maintain its intra-amoebal replication niche and to ultimately escape from the succumbed host. Several of these features, including extracellular enzymes and motility, are considered minor virulence factors as they also play a role in human disease. The study suggests that the aquatic milieu provides a training ground for V. cholerae and that adaptation towards amoebal predators might have contributed to V. cholerae's emergence as a major human pathogen.

Exosomes Derived from Mesenchymal Stem Cells Alleviate Atopic Dermatitis in Mouse Model

ExoCoBio Inc., based in South Korea, has reported publishing a scientific paper indicating that stem cell-derived exosomes dramatically relieve atopic dermatitis and inhibit a variety of inflammatory targets in Stem Cell Research and Therapy. The open-access article, published online on July 11, 2018, is titled “Exosomes Derived from Human Adipose Tissue-Derived Mesenchymal Stem Cells Alleviate Atopic Dermatitis.” According to the paper, the symptoms of mice having severe atopic dermatitis were significantly improved after administration of stem cell-derived exosomes intravenously or subcutaneously, so that the level of serum immunoglobulin E (IgE), the number of eosinophils in blood, and the number of mast cells in the skin lesion were decreased. It has also been found that the number of inflammatory dendritic epidermal cells (IDECs), which are not found in normal skin but cause an allergic inflammatory response in atopic dermatitis lesions, also significantly decreased to a normal skin level after administration of stem cell-derived exosomes. In addition, the improvement of the symptoms by stem cell-derived exosomes was comparable to that of a steroid drug, prednisolone. While atopic dermatitis is a chronic disease depreciating the quality of life, there is no fundamental treatment to treat it yet. Currently available atopic treatments, such as anti-histamines, steroids, and immunosuppressive drugs, have various side effects such as impaired immune systems, liver & kidney damage during long-term administration, etc. Inhibitory antibodies against various inflammatory cytokines such as IL-4, IL-31, TNF-alpha and IL-23 are under development or on the market to relieve atopic dermatitis symptoms. However, these treatments just relieve atopic dermatitis by blocking the function of one or two specific proteins.

Researchers Discover How Body Regenerates Blood Vessel Lining; Atf3 Gene Seems Key; Findings Could Lead to New Methods to Help Prevent Clots and Repair Damage Linked to Stents

Normal wear and tear damages the blood vessel lining, which is called the endothelial lining. The body, however, has the ability to initiate molecular activity that regenerates and repairs this damage. Now, researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA in California have, for the first time, followed this regeneration in progress and identified the genes and proteins responsible for spurring it. Their findings could eventually lead to novel methods to repair more severe blood vessel damage, including damage that can result from placing stents — metal or plastic mesh tubes that open blocked or narrow blood vessels. The study, led by Dr. Luisa Iruela-Arispe, a UCLA Professor of Molecular, Cell and Developmental Biology and a member of the UCLA Broad Stem Cell Research Center, was published online on August 2, 2018 in Cell Stem Cell. The article is titled “Endothelial Regeneration of Large Vessels Is a Biphasic Process Driven by Local Cells with Distinct Proliferative Capacities.” “The well-being of the endothelial lining is really fundamental for health,” Dr. Iruela-Arispe said. “Understanding how to keep this lining in good shape will help us make progress in treating multiple disease states.” In blood vessels snaking throughout the body — circulating blood to organs and extremities — the endothelial lining acts as a filter and a wall. The composition of the lining, which includes anti-clotting protein on its surface, generally prevents blood from clotting as it moves through the body, and controls what materials — such as inflammatory cells — can enter and exit the blood flow.

UCLA Research Reveals Key Difference in How Stem Cells Act When Stressed Versus When at Rest

Stem Cell Research and Jonsson Comprehensive Cancer Center in California have discovered an important distinction in how blood-forming stem cells are supported by their micro-environments during rest and after injury. The body appears to switch the type of cell that produces a single growth factor during healthy times and during stress or injury — for instance, radiation treatment for cancer. The results could have implications for treating cancer, when people’s blood-forming stem cells may be substantially depleted, and for people undergoing certain types of transplants. The study, led by Dr. John Chute, a member of the center and a Professor of Hematology/Oncology at the David Geffen School of Medicine at UCLA, was published in Cell Stem Cell. The article is titled “Distinct Bone Marrow Sources of Pleiotrophin Control Hematopoietic Stem Cell Maintenance and Regeneration.” Blood-forming, or hematopoietic, stem cells can differentiate into various types of mature blood elements — white blood cells, red blood cells, and platelets. They live in “vascular niches” in the bone marrow, where different types of surrounding cells support them, partly by secreting compounds called growth factors. The UCLA study focused on a growth factor called pleiotrophin (PTN). Dr. Chute and his team had previously discovered pleiotrophin, but had yet to determine which type of cells secrete it. “In stem cell research, two important questions are, ‘What are the microenvironment cells that regulate stem cells,’ and ‘How do they do it?’” Dr. Chute said. To find out, the team bred mice that lacked pleiotrophin expression in various types of bone marrow cells — including endothelial cells, which line the blood vessels, and stromal cells, which make up connective tissue.

Researchers Identify Link Between Gut Bacteria and Eating for Pleasure, As Opposed to for Hunger

A study of 63 healthy people showed that those with elevated microbiome levels of the metabolite indole (image) -- produced when gut bacteria break down the amino acid tryptophan -- had stronger function and connectivity in specific areas of the brain's reward network. Such activity in the brain indicates that a person is more prone to "hedonic eating," or eating for pleasure rather than for hunger. Those with higher levels of indole also were more likely to have food addiction, as determined by questionnaires they completed. Certain areas of the brain's reward network have long been known to drive eating behaviors. In particular, the nucleus accumbens -- which processes reward stimuli such as food -- and the amygdala -- which helps regulate emotions -- are activated when people are hungry or eating. In this study, people with higher indole levels showed stronger function and connectivity in these two areas. Higher function and connectivity in the brain's reward system could indicate an overactive reward system that promotes and reinforces overeating. Such overactivity of the reward system in obese individuals with food addiction has been reported in previous research. The researchers obtained functional MRI brain imaging from the healthy participants. They collected and analyzed fecal samples in order to determine the presence of particular gut metabolites. The subjects completed questionnaires that measured their propensity for food addiction. The study -- the first in humans to show the association between specific metabolites produced by gut bacteria and overeating behaviors -- suggests that indole, or gut bacteria's ability to produce it, could contribute to such behaviors.

3D Images of Skin Molecule Involved in Temperature Sensation Could Lead to New Treatments for Skin Diseases

Columbia University biomedical researchers have captured close-up views of TRPV3, a skin-cell ion channel protein that plays important roles in sensing temperature, itch, and pain. In humans, defects in this protein can lead to skin diseases such as atopic dermatitis (a type of eczema), vitiligo (uneven skin coloration), skin cancer, and rosacea. All vertebrate DNA, including the woolly mammoth genome, contains the TRPV3 gene. Though the mammoths lived in extremely cold environments, they descended from elephants that lived in the tropics. Researchers think that changes in the TRPV3 genes of mammoths may have helped them withstand lower temperatures. The article was published online on August 20, 2018 in Nature Structural & Molecular Biology, and is titled "Structure and Gating Mechanism of the Transient Receptor Potential Channel TRPV3." Dr. Alexander Sobolevsky's lab at Columbia University Irving Medical Center used a powerful imaging technique called cryo-electron microscopy to take pictures of TRPV3 molecules. Initial 2D images were collected by freezing the molecules in an extremely thin, clear layer of ice and bombarding them with electrons. The researchers then used computational tools to convert the 2D images into detailed molecular 3D models. This is the first time scientists have gotten a glimpse of TRPV3 in atomic detail. The researchers were able to get images of the protein in two states, revealing how the channel opens and closes to let ions flow into skin cells. This exchange of ions prompts the body to react to sensations such as pain, itchiness, and changes in temperature. The group also discovered how a small molecule with anti-cancer properties called 2-APB interacts with and controls the function of this channel.

Newly Identified Key Lymph Node Structure Was “Hiding in Plain Sight”

For the first time in decades, researchers have identified a new “micro-organ” within the immune system - and they say it's an important step towards understanding how to make better vaccines. In a study published online on August 22, 2018 in Nature Communications, scientists at Australia's Garvan Institute of Medical Research have identified where the immune system “remembers” past infections and vaccinations - and where immune cells gather to mount a rapid response against an infection the body has seen before. The open-access article is titled “Memory B Cells Are Reactivated in Subcapsular Proliferative Foci of Lymph Nodes.” The structure was only discovered when the researchers “made movies” of the immune system in action, using sophisticated high-resolution 3D microscopy in living animals. Jam-packed with immune cells of many kinds, the structure is strategically positioned to detect infection early, making it a one-stop shop for fighting a “remembered” infection - fast. We have known for millennia that people exposed to an infection are often protected from getting the same infection again - ever since the Plague of Athens in 430 BC, where plague survivors were noted to have developed immunity against reinfection. Yet, major questions remain about how the body can fight back fast when it encounters an infection that it has been previously exposed to (through a vaccine or through an earlier infection). The researchers reveal the existence of thin, flattened structures extending over the surface of lymph nodes in mice. These dynamic structures are not always present: instead, they appear only when needed to fight an infection against which the animal has previously been exposed.

Combination Immunotherapy Shrinks Brain Melanoma Metastases, Providing Durable Responses in Stage 4 Patients; Clinical Study Results Reported in NEJM

Combination immunotherapy shrank melanoma that has spread to the brain in more than half of the patients in a clinical trial reported online on August 23, 2018 in the New England Journal of Medicine led by an investigator at The University of Texas MD Anderson Cancer Center. The article is titled “Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain.” Of 94 patients in the single-arm study combining checkpoint inhibitors ipilimumab and nivolumab, at a minimum follow-up of nine months and a median of 14 months, 24 (26 percent) had a complete response, 28 (30 percent) had a partial response, and 2 (2 percent) had stable disease. "As treatment for stage 4 melanoma has improved greatly in recent years, our patients with metastases to the brain have remained the group most in need, they've had the worst prognosis, so we are very excited about these results," said the national study's principal investigator and lead author Hussein Tawbi, MD, PhD, Associate Professor of Melanoma Medical Oncology at MD Anderson. "This practice-changing study proved that you can start with immunotherapy first with these patients, tackling both brain and extracranial disease at the same time," Dr. Tawbi said. "And it opens up new opportunities for development of systemic therapies for metastatic melanoma." About 40 percent of patients with stage 4 melanoma have brain metastases at diagnosis, and 75 percent eventually develop the condition, which previously was so intractable to treatment that these patients were routinely excluded from clinical trials of new drugs. Median overall survival of patients with brain metastases has been four to five months. In the reported study, at nine months, 59.5 percent of patients with brain tumors had not progressed.

Capricor Therapeutics Presents Results of Studies of CAP-2003 (Including Exosomes) at Gordon Research Conference on Extracellular Vesicles

On August 21, 2018, it was announced that at the Gordon Research Conference on Extracellular Vesicles in Newry, Maine, Capricor Therapeutics (NASDAQ: CAPR) presented research findings on the mechanism of action and the immunomodulatory capacities of CAP-2003, the company’s investigational therapy comprised of proprietary extracellular vesicles (EVs), including exosomes, which are derived from cardiosphere-derived cells (CDC-EVs). Capricor is developing CAP-2003 as a therapeutic platform for treating diseases involving inflammation and fibrosis. The Gordon Research Conference on Extracellular Vesicles is focused on cutting-edge research on the biogenesis, molecular composition, functions, physio-pathological roles, and potential clinical applications of extracellular vesicles. Gordon Research Conferences are a group of prestigious international scientific conferences that are at the forefront of research in the biological, chemical, and physical sciences, and their related technologies. “The pre-clinical studies presented at the Gordon Research Conference further elucidate Capricor’s progress in developing this exciting new class of therapeutics, the exosomes which comprise our investigational therapy, CAP-2003,” said Linda Marbán, PhD, Capricor CEO. “The studies further demonstrate that exosomes may be the active pharmaceutical ingredient (API) in CAP-1002, our cell therapy product, because these extracellular vesicles serve as cellular-messengers, altering function and physiology to balance inflammation so that cellular repair can be facilitated.” In the first study, Capricor compared CAP-2003 with exosomes made from mesenchymal stem cells (MSCs).

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