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June 11th, 2019

A “One-Two Punch” to Wipe Out Cancerous Ovarian Cells; New Two-Pronged Approach Causes Premature Aging and Death of Ovarian Cancer Cells; Clinical Trials Being Considered for Ovarian Cancer & Triple-Negative Breast Cancer

Researchers from the University of Montreal Hospital Research Centre (CRCHUM) have developed a two-step combination therapy to destroy cancer cells. In a study published online on June 11, 2019 in Nature Communications, they show the superior therapeutic effectiveness of the "one-two punch" on cells of ovarian cancer patients, based on manipulation of the state of cellular aging. Their open-access article is titled “Exploiting Interconnected Synthetic Lethal Interactions Between PARP Inhibition and Cancer Cell Reversible Senescence.” “With time, our cells age and enter a phase called cellular senescence. These senescent cells stop proliferating, build up in the body, and cause the development of diseases such as cancer. In recent years, the scientific community has tried to heal these aging-related pathologies by targeting and destroying senescent cells. "In the case of epithelial ovarian cancer (EOC)--the most common and lethal ovarian cancer--we act in two stages. First, we force the cancer cells to age prematurely, i.e., we force them into senescence. This is the first therapeutic punch. We throw our second punch using senolysis, destroying and eliminating the senescent cancer cells. This strategy requires excellent coordination of the two steps," explained Francis Rodier, PhD, a researcher at the CRCHUM and professor at the Université de Montréal. The team of researchers, led by Dr. Rodier and his colleague Anne-Marie Mes-Masson, PhD, discovered that EOC cells enter senescence following chemotherapy in combination with PARP inhibitors. PARPs are enzymes that help repair damage to DNA. By blocking PARPs, PARP inhibitors prevent cancer cells from repairing their DNA, stop them from proliferating, and cause them to age prematurely.

Noninvasive Test of Cell-Free Methylated DNA Markers Shows High Sensitivity and Specificity in Detection of Nasopharyngeal Carcinoma (NPC); Early Study Results Presented at ASCO 2019 by Laboratory for Advanced Medicine (LAM)

(by Michael D. O’Neill, Editor & Publisher of BioQuick News, based on interview of, and materials provided by, Dr. Dhruvajyoti Roy)--One of the highly significant abstracts presented at the recent American Society of Clinical Oncology (ASCO) Annual Meeting 2019 in Chicago (May 31-June 4) described impressive preliminary data on the liquid biopsy detection of nasopharyngeal carcinoma (NPC), which is one of the most prevalent malignancies in Southeast Asia, the Mediterranean, and the Arctic. Using a proprietary test of cell-free DNA methylation markers, the Laboratory for Advanced Medicine (LAM), headquartered in Irvine, California, showed preliminary data demonstrating high sensitivity and high specificity in the early detection of NPC using its DNA methylation test (the IvyGene test). The LAM study was conducted using samples obtained from 168 subjects, including 59 subjects diagnosed with NPC (Stages I to IV), 14 subjects diagnosed with benign nasopharyngeal disease and 43 healthy subjects. From the 59 subjects diagnosed with NPC, a total of 57 subjects were correctly identified (sensitivity of 97%), with little difference between the sensitivity of detecting Stage I to Stage IV NPC (range 92% to 100%). Additionally, for subjects diagnosed with other cancers, a total of 86% of subjects were correctly identified as negative for NPC. Finally, all 43 samples drawn from healthy donors and all 14 samples drawn from subjects diagnosed with benign nasopharyngeal disease were correctly identified as negative for NPC (combined specificity of 100%).

Scorpion Venom Strategies Designed to Save Precious Venom Components for Critical Needs

Replenishing venom takes time and energy - so it pays to be stingy with stings. According to researchers at the Australian National Institute of Tropical Health and Medicine, scorpions adapt their bodies, their behavior, and even the composition of their venom, for efficient control of prey and predators. In an open-acccess article published online on June 6, 2019 in Frontiers in Ecology and Evolution, the scientists say it's not just the size of the stinger, but also how it's used that matters. "Scorpions can store only a limited volume of venom, that takes time and energy to replenish after use," says lead author Edward Evans, PhD. "Meanwhile the scorpion has a reduced capacity to capture prey or defend against predators, so the costs of venom use are two-fold." As a result, over 400 million years of evolution, scorpions have developed a variety of strategies to minimize venom use. The most obvious of these is to avoid using venom at all. "Research has shown the lighter, faster male specimens of one species are more likely to flee from danger compared to the heavier-bodied females, rather than expend energy using toxins," notes Dr. Evans. "Others -- particularly burrowing species -- depend instead on their large claws or 'pedipalps,” and have a small, seldom-used stinging apparatus." When immobility, threat, or lively prey forces venom use, scorpions can adjust the volume they inject - both within each sting and through the application of multiple stings. "Scorpions can hold prey in their pedipalps and judiciously apply stings, just until it stops struggling." At the other extreme, when the survival stakes are high, some species abandon precision and spray their venom through the air.

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.

June 10th

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.