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Early Life Stress and High Levels of FKBP5 Protein Heighten Anxiety-Like Behavior, Lending Support to Importance of Gene-Environment Interactions in Neuropsychiatric Disease Risk

Researchers continue to dig for molecular clues to better understand how gene-environment interactions influence neuropsychiatric disease risk and resilience. An increasing number of studies point to a strong association between the FKBP5 gene and increased susceptibility to depression, anxiety, post-traumatic stress disorder, and other mental health disorders. Adding to the growing evidence, a new preclinical study by University of South Florida (USF) neuroscientists finds that anxiety-like behavior increases when early life adversity combines with high levels of FKBP5 - a protein capable of modifying hormonal stress response. Moreover, the researchers demonstrate this genetic-early life stress interaction amplifies anxiety by selectively altering signaling of the enzyme AKT in the dorsal hippocampus, a portion of the brain primarily responsible for cognitive functions like learning and memory. While more research is required, the study suggests that FKBP5 may be an effective target for treating anxiety and other mood disorders. The findings were published online on June 4, 2019 in the International Journal of Molecular Sciences. The open-access article is titled “Early Life Stress and High FKBP5 Interact to Increase Anxiety-Like Symptoms through Altered AKT Signaling in the Dorsal Hippocampus.” "We know that the combination of genetic variations and environmental factors can make people either more or less susceptible to mental illness -- even when they experience the same types of trauma," said senior author Laura Blair, PhD, Assistant Professor of Molecular Medicine at the USF Health Byrd Alzheimer's Center. Postdoctoral scholar Marangelie Criado-Marrero, PhD, was lead author of the study.

Fibrinogen Plays Role in Body’s Defense Mechanisms by Inhibiting MMP2 Enzyme

A finding from University of Alberta (U of A) researchers in Canada is shining new light on the role fibrinogen has in regulating a natural defense mechanism in the body. The discovery is hoped to contribute to improved diagnosis and treatments for patients in a variety of diseases ranging from inflammation, to heart failure, to cancer. Fibrinogen (image) is a well-known protein that is essential for wound healing and blood clotting in the body. But a study published online on March 13, 2019 in Scientific Reports shows it is also a natural inhibitor of an enzyme named MMP2 that is important for normal organ development and repair. The open-access article is titled” Identification of Fibrinogen As a Natural Inhibitor of MMP-2.” MMP2 is typically found in increased levels in the blood in disease conditions. The researchers believe a vital function of fibrinogen is to allow or disallow the MMP2 enzyme to carry out its normal functions. However, high levels of fibrinogen may excessively inhibit MMP2, which could result in arthritic and cardiac disorders similar to those seen in patients with MMP2 gene deficiency. "Whenever there's an infection or there's an injury, fibrinogen can go up by tenfold in the blood. So, at that concentration it would excessively inhibit MMP2," said Hassan Sarker, a PhD candidate at the U of A and study lead author. "Binding of fibrinogen in the circulation to MMP2 enzymes prevents them from docking to target tissues," added Carlos Fernandez-Patron, PhD, a Professor of Biochemistry at the U of A, who directed this research. "It affects their activity and we don't know exactly whether that results in a beneficial or deleterious effect. It's something we need to investigate." The finding opens a new window into the inner workings of the MMP family of enzymes.

Promising New Therapy (LIF Inhibitor) with Dual Mechanism of Action to Eliminate Cancer Stem Cells & Activate Immune System Is Now In Clinical Development; Study Exposes Parallels Between LIF Roles in Embryogenesis & in Cancer

Results from a study spearhead by researchers at the Vall d´Hebron Institute of Oncology (VHIO) in Barcelona, Spain, show that the blockade of the multi-functional cytokine LIF (image)induces tumor-infiltrating T Cells to home in on and eliminate cancer. Reported on June 11, 2019 in Nature Communications, this research was led by corresponding and co-first author Joan Seoane, PhD, Co-Program Director of Preclinical and Translational Research at VHIO, and ICREA Research Professor, and has now culminated in a Phase I clinical trial currently assessing the safety and efficacy of LIF (leukemi inhibitory factor) inhibitors in patients across three sites: the Vall d'Hebron University Hospital (HUVH), Memorial Sloan Kettering Cancer Center (MSKCC - New York, USA), and the Princess Margaret Cancer Center (Toronto, Canada). The open-access article is titled “LIF Regulates CXCL9 In Tumor-Associated Macrophages and Prevents CD8+ T Cell Tumor-Infiltration Impairing Anti-PD1 Therapy.” Developed by VHIO, the novel agent MSC-1 inhibits LIF and has now been shown to have a dual mechanism of action. First, in tumors expressing high levels of LIF, the protein LIF promotes the proliferation of cancer stem cells. LIF blockade eliminates these tumor-initiating stem cells, putting the brakes on metastatic cell spread and cancer recurrence. Additionally, elevated LIF expression disables the anti-tumor alarm system and stops the immune system from thwarting cancer's plans. Blocking LIF reactivates the alarm to call an anti-tumoral immune response.

Milestone of Stem-Cell-Derived Exosome Program Achieved by Avalon Globocare Corp; Will Allow Company to Enter Its Next Phase of Commercializing Clinical-Grade Exosome Products; Skin Care and Wound-Healing Products Will Be First Developed

On June 10, 2019, Avalon GloboCare Corp. (AVCO), a leading global developer of cell-based technologies and therapeutics, announced it has achieved a major milestone in bio-production standardization of clinical-grade stem-cell-derived exosomes. The standardized procedure was a direct result of the previously announced co-development program (https://ir.avalon-globocare.com/press-releases/detail/28/avalon-globocar...) at Weill Cornell Medicine with Yen-Michael Hsu, MD, PhD, as principal investigator. The process has been co-developed and operated within Weill Cornell's cGMP-certified cell therapy facility jointly accredited under the Foundation of Accreditation for Cellular Therapy (FACT), American Association of Blood Banking (AABB), College of American Pathologists (CAP), as well as Clinical Laboratory Improvement Amendment (CLIA). Avalon will hold a press conference to announce the launch of its exosome product commercialization plan, including a series of over-the-counter skincare and wound-healing products with Avalon's Clinical-Grade Tissue-Specific EXosomes as additives (ACTEX), on June 15, 2019 during the 2nd International Aesthetic Industry Conference in Chengdu, China -- the largest conference of its kind in Asia. In addition to product commercialization, this standardization of clinical-grade stem-cell-derived exosomes will lead to parallel development of Avalon's clinical programs, including AVA-202 and AVA-203, for angiogenic/orthopedic regeneration, as well as treatment of fibrotic diseases. "We are pleased to complete such a significant developmental milestone of our exosome program," stated David Jin, MD, PhD, CEO and President of Avalon GloboCare and Co-CEO of its subsidiary GenExosome Technologies.

Exosomes from Stem Cells Show Promise Against Multiple Sclerosis in Animal Study; First Human Trials Being Planned for Type 1 Diabetes, Then, If Successful, for Other Autoimmune Diseases, Including MS

A nanotechnology treatment derived from bone marrow stem cells has reversed multiple sclerosis symptoms in mice and could eventually be used to help humans, according to a new study led by University of California, Irvine (UCI) researchers. "Until now, stem cell therapies for autoimmune and neurodegenerative diseases have produced mixed results in clinical trials, partly because we don't know how the treatments work," said corresponding author Weian Zhao (photo), PhD, an Associate Professor of Pharmaceutical Sciences and Biomedical Engineering who is affiliated with the Sue & Bill Gross Stem Cell Research Center. "This study helps unravel that mystery and paves the way for testing with human patients." In past experiments, intravenously injected stem cells - taken from bone marrow and activated with interferon gamma, an immune system protein - often became trapped in filter organs before reaching their target. For this study, published online on May 22, 2019 in ACS Nano, researchers avoided that problem by extracting nano-sized particles called exosomes from the stem cells and injecting them into rodents with MS. The ACS Nano article is titled “Stem Cell-Derived Exosomes As Nanotherapeutics for Autoimmune and Neurodegenerative Disorders.” Loaded with anti-inflammatory and neuroprotective RNA and protein molecules, the exosomes were able to slip through the blood-spinal cord barrier. In addition to rejuvenating lost motor skills and decreasing nerve damage caused by MS, the exosome contents normalized the subjects' immune systems, something conventional drugs can't do, said study co-lead author Reza Mohammadi, a UCI doctoral candidate in materials science & engineering.

Scorpion Venom Toxins Found to Have Components with Anti-Bacterial Activity; Stanford Scientists Synthesize These Components in the Lab; May Point Way to New Weapons Against Increasingly Drug-Resistant Bacteria

A scorpion native to Eastern Mexico may have more than just toxin in its sting. Researchers at Stanford University and in Mexico have found that the venom also contains two color-changing compounds that could help fight bacterial infections. The team not only isolated the compounds in the scorpion's venom, but also synthesized them in the lab and verified that the lab-made versions killed staphylococcus and drug-resistant tuberculosis bacteria in tissue samples and in mice. The findings, published online on June 10, 2019 in PNAS, highlight the potential pharmacological treasures awaiting discovery in the toxins of scorpions, snakes, snails, and other poisonous creatures. The PNAS article is titled “1,4-Benzoquinone Antimicrobial Agents Against Staphylococcus Aureus and Mycobacterium tuberculosis Derived from Scorpion Venom.” "By volume, scorpion venom is one of the most precious materials in the world. It would costs $39 million to produce a gallon of it," said study senior author Richard Zare (https://web.stanford.edu/group/Zarelab/about.html), PhD, who led the Stanford group. "If you depended only on scorpions to produce it, nobody could afford it, so it's important to identify what the critical ingredients are and be able to synthesize them." Dr. Zare worked with his colleagues in Mexico, including Lourival Possani, PhD, a Professor of Molecular Medicine at the National University of Mexico, whose students caught specimens of the scorpion Diplocentrus melici for study. "The collection of this species of scorpion is difficult because during the winter and dry seasons, the scorpion is buried," Dr. Possani said. "We can only find it in the rainy season." For the past 45 years, Dr. Possani has focused on identifying compounds with pharmacological potential in scorpion venom.

Rhes Protein Initiates Construction of Nanotubes That Enable Travel of Huntington’s Disease Protein from Cell to Cell

A toxic protein (huntingtin) linked to Huntington’s disease can move from neuron to neuron through a nanotube tunnel whose construction is initiated by a protein called Rhes, say scientists at Scripps Research-Florida. The finding, by Scripps Research neuroscientist Srinivasa Subramaniam, PhD, improves understanding of how and why this disease attacks and destroys certain brain cells. The research was published online on May 10, 2019 in Journal of Cell Biology. The article is titled “Rhes Travels from Cell to Cell and Transports Huntington Disease Protein Via TNT-Like Cellular Protrusions.” “We are excited about this result because it may explain why the patient gets the disease in this area of the brain called the striatum,” says Dr. Subramaniam, an Associate Professor in the Department of Neuroscience at Scripps Research-Florida. People with Huntington’s disease inherit a mutant gene that codes for an aberrant protein that is somehow complicit in destroying brain cells. Scientists discovered this protein in 1993, but are still piecing together its role in this degenerative disease. Scans show Huntington’s disease brains are shrunken and degraded. As the neurons deteriorate, people lose motor control, they can have emotional problems, and their thinking and memory suffer. Symptoms usually begin around age 30 to 40 and last 15 to 20 years until death. A rarer and more aggressive form of the disease affects children, cutting their childhood and their lives short. About 3 to 7 people out of 100,000 have the disease and it has mostly affected those with European ancestry. However, Dr. Subramaniam believes the disease is underreported in other areas, such as India. “There is a lot of stigma associated with the disease,” says Subramaniam.

Additional Findings Suggest Diet Changes Could Lead to Better Prevention and Management of Type 2 Diabetes

Could changing what we eat lower the chances of developing type 2 diabetes? Studies presented at Nutrition 2019 will examine how consuming certain foods, vitamins and even the order in which we eat can affect blood sugar levels and risk of developing 2 diabetes. Nutrition 2019 is being held June 8-11, 2019 at the Baltimore Convention Center. In a study of 2,717 young adults in the US with long-term follow-up, people who increased the amount of fruits, vegetables, whole grains, nuts and vegetable oils in their diet over 20 years had a 60 percent lower risk of type 2 diabetes compared to those with a small decrease in plant foods. The findings suggest that long-term shifts toward a more plant-centered diet could help prevent diabetes. Yuni Choi, PhD candidate, University of Minnesota-Twin Cities, will present this research on Tuesday, June 11, from 11 - 11:15 a.m. in the Baltimore Convention Center, Ballroom IV. The presentation is titled “Life Course Change Towards a Plant-Centered Diet and Incidence of Type 2 Diabetes: The Coronary Artery Risk Development in Young Adults (CARDIA) Study” (https://www.eventscribe.com/2019/ASN/fsPopup.asp?Mode=presInfo&Presentat...). Findings from a second study examining three large cohorts of US health professionals suggest that people with higher intakes of vitamins B2 and B6 from food or supplements have a lower risk for type 2 diabetes. The study, which included more than 200,000 people, also revealed that consuming higher levels of vitamin B12 from foods was associated with a higher type 2 diabetes risk, which may be due to consumption of animal products. Kim V. E. Braun, PhD, Erasmus University Medical Center, presented this research on Sunday, June 9, from 3:15 - 3:30 p.m. in the Baltimore Convention Center.

Large International Study Finds Diabetes Drug (Dulaglutide) Cuts Cardiovascular & Kidney Problems in Older Patients with Type 2 Diabetes; Dulaglutide Is Glucagon-Like Peptide-1 Receptor Agonist; Two Articles in The Lancet

A clinical trial that followed more than 9,900 people in 24 countries has found that the drug dulaglutide reduced cardiovascular events and kidney problems in middle-aged and older people with Type 2 diabetes. During more than five years of follow-up, cardiovascular events like heart attacks and strokes were reduced by 12% in people taking dulaglutide compared to people taking a placebo. This effect was seen in both men and women with or without previous cardiovascular disease. In addition, during the same period, the drug reduced the development of kidney disease by 15%. The trial was led by the Population Health Research Institute (PHRI) of McMaster University and Hamilton Health Sciences, both in Hamilton, Ontario, Canada. Two papers describing the cardiovascular and kidney results of the trial were published on June 9, 2019 in The Lancet from the study called the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. The two articles are titled “Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND): a Double-Blind, Randomised Placebo-Controlled Trial” and “Dulaglutide and Renal Outcomes in Type 2 Diabetes: an Exploratory Analysis of the REWIND Randomised, Placebo-Controlled Trial.” "Compared to others, people with diabetes have twice the rate of cardiovascular events like heart attacks and strokes, and up to 40% of people with diabetes develop kidney disease," said Hertzel C. Gerstein (photo), MD, principal investigator for the study, Professor of Medicine at McMaster and Deputy Director of the PHRI. "The REWIND trial shows that dulaglutide can safely reduce these events while improving diabetes control and modestly lowering weight and blood pressure in middle-aged people with Type 2 diabetes."

Experimental Drug Delays Type 1 Diabetes in People at High Risk; NIH-Funded Study Shows That Immunotherapy with Monoclonal Anti-CD3 Antibody (Teplizumab) Slows Progression to Clinical Disease by Two Years or More

A treatment affecting the immune system effectively slowed the progression to clinical type 1 diabetes in high-risk individuals, according to findings from National Institutes of Health-funded research. The study is the first to show that clinical type 1 diabetes can be delayed by two or more years among people who are at high risk. These results were published online on June 9, 2019 in The New England Journal of Medicine and presented at the American Diabetes Association Scientific Sessions (June 7-11) in San Francisco. The NEJM article is titled “An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes.” The study, involving treatment with an anti-CD3 monoclonal antibody (teplizumab), was conducted by Type 1 Diabetes TrialNet (https://www.trialnet.org/), an international collaboration aimed at discovering ways to delay or prevent type 1 diabetes. Researchers enrolled 76 participants ages 8-49 who were relatives of people with type 1 diabetes, had at least two types of diabetes-related autoantibodies (proteins made by the immune system), and abnormal glucose (sugar) tolerance. Participants were randomly assigned to either the treatment group, which received a 14-day course of teplizumab, or the control group, which received a placebo. All participants received glucose tolerance tests regularly until the study was completed, or until they developed clinical type 1 diabetes - whichever came first. During the trial, 72% of people in the control group developed clinical diabetes, compared to only 43% of the teplizumab group. The median time for people in the control group to develop clinical diabetes was just over 24 months, while those who developed clinical diabetes in the treatment group had a median time of 48 months before progressing to diagnosis.

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