National University of Ireland Galway

Researchers are exploring a potential new therapeutic approach for triple negative breast cancer treatment. Medical researchers are working on the design of nitric oxide scavengers to form a new treatment approach for this aggressive form of breast cancer. Researchers are exploring a potential new therapeutic approach for triple negative breast cancer treatment. Amir Abdo Alsharabasy, a CÚRAM doctoral candidate working in the laboratory of Professor Abhay Pandit, is working on the design of nitric oxide scavengers to form a new treatment approach for this aggressive form of breast cancer. Triple-negative breast cancer is invasive breast cancer that does not respond to hormonal therapy medicines or the current medicines that target the HER2 protein. Triple-negative breast cancer is usually more aggressive, harder to treat, and more likely to recur than cancers that are hormone receptor-positive or HER2-positive. "Nitric oxide is one of the prominent free radicals produced by the tumor tissue," explains Amir, "It, at certain concentrations, plays a significant role in breast cancer progression by inducing the cancer cells to spread to other parts of the body Our goal is to develop injectable hydrogel formulations, which can reduce the levels of, or 'scavenge' the nitric oxide, while enhancing the generation of carbon monoxide, so that we can potentially design a new treatment approach for triple negative breast cancer." Nitric oxide interacts with different components of the large network of proteins and other molecules that surround, support, and give structure to tumor cells and tissues in the body. Hyaluronic acid is one of the main components of this network and is the material of choice for fabricating these hydrogels. "HA plays multiple roles in tumour tissues" says Amir. "However, its interactions with nitric oxide have not been thoroughly investigated. The study, recently published in Biomacromolecules, attempts to understand the mechanism of these interactions and the different effects on nitric oxide levels and migration of breast cancer cells." The study is supervised by Prof Abhay Pandit, Scientific Director of CÚRAM, and was published with collaborators Dr Sharon Glynn from the Lambe Institute for Translational Research and Dr Pau Farras from the School of Biological and Chemical Sciences in the Ryan Institute at the National University of Ireland Galway, The work investigated the ability of HA to scavenge nitric oxide. The team found that the conversion of nitric oxide to certain nitrogen centred free radicals causes the HA to break down, which further inhibits the nitric oxide induced migration of cancer cells in the tumor environment. Collectively, these results help toward understanding the involvement of HA in nitric oxide induced cell migration and suggests the potential use of modified HA, as a key material in different biomedical applications. Commenting on the study, Professor Abhay Pandit, said: "While the recent progress in research about the roles of nitric oxide with tumour progression resulted ultimately in a number of ongoing clinical trials for evaluating the effects of NO-synthase inhibitors, we are focusing on NO itself trying to avoid the side effects/reactions of these inhibitors." Amir Abdo Alsharabasy received a BSc in Chemistry & Biochemistry, Mansoura University, Egypt, MSc in Biochemistry, Helwan University, Egypt and MSc in Biological and Bioprocess Engineering, Sheffield University, U.K. He spent some time working as a research assistant in Radiation Chemistry Department at NCRRT, Egypt. He was recently awarded two awards for his research. The first was a presentation award from the Second International Conference "Therapeutic Applications of Nitric Oxide in Cancer and Inflammatory-related Diseases for his talk on the interactions between nitric oxide and hemin and their implications in the nitration of proteins in breast cancer cells. The second was an EMBO Scientific Exchange Grant to support a visit of the laboratory of Dr. Lasse Jensen in Linköping Univ., Sweden.

Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones. COVID-19 Infection Doesn’t Seem to Confer Strong Antibody Response A new study out of Northwestern University published in Scientific Reports shows that previous exposure to SARS-CoV-2, the virus that causes COVID-19, doesn’t guarantee a high antibody response. It also suggests that a robust antibody response isn’t guaranteed after a single dose of the vaccine. The data supports full vaccination, even for people who caught COVID-19. The researchers tested blood samples from adults who tested positive for COVID-19 to evaluate how long the immunity benefits of the Pfizer-BioNTech and Moderna mRNA vaccines lasted and how well they protect against variants. The participants submitted blood samples two to three weeks after their first and second vaccine doses and two months after the second dose. “When we tested blood samples from participants collected about three weeks after their second vaccine dose, the average level of inhibition was 98%, indicating a very high level of neutralizing antibodies,” said Thomas McDade, a Northwestern biological anthropologist who worked with pharmacologist Alexis Demonbreun, on the study. They also tested emerging variants, including Alpha (UK), Beta (South Africa), and Gamma (Brazil). They found the inhibition levels to the variants were significantly lower, ranging from 67% to 92%. Testing samples two months after the second dose, the investigators found antibody responses dropped by approximately 20%. The people with clinically confirmed COVID-19 and multiple symptoms had a higher response level than people who tested positive but had mild symptoms or were asymptomatic. “Our study shows that prior exposure to SARSo-CoV-2 does not guarantee a high level of antibodies, nor does it guarantee a robust antibody response to the first vaccine dose,” McDade said. “For people who had mild or asymptomatic infections, their antibody response to vaccination is essentially the same as it is for people who have not been previously exposed.” Asymptomatic COVID-19 May Still Cause Damage A research study published in the Annals of Internal Medicine by Eric Topol and Daniel Oran from Scripps Research Translational Institute suggests that even asymptomatic COVID-19 infections may cause lung damage. The research began by evaluating data from patients aboard the cruise ship Diamond Princess which was quarantined off the coast of Japan in the earliest part of the pandemic. Of the 104 patients who tested positive on the ship, 76 were asymptomatic. However, CT scans found 54% had lung abnormalities known as ground glass opacities, which are indicative of fluid build-up in the lungs. It also included data from other parts of the world. Predicting Alzheimer’s Through a New Brain Model A study from investigators with Brigham and Women’s Hospital has the potential to predict Alzheimer’s progress. They created an induced pluripotent stem cell (iPSC) line from more than 50 different people that also had longitudinal clinical data, quantitative neuropathology data, and genetic and molecular brain tissue profiling. They turned the stem cells into brain cells and analyzed the molecular pathways of the living neurons in a Petri dish. They identified specific types of beta-amyloid and tau, both abnormal proteins associated with cognitive decline and Alzheimer’s, as well as signaling pathways that affected the production of the proteins. The people’s different genetic backgrounds created different profiles of beta-amyloid and tau, which are predictive in nature. Of interest as well is the possibility that antibody drugs against these proteins, such as Biogen’s aducanumab, may respond differently to different species of the proteins, the test may be used to determine what patients the drugs would be effective for. Using Electrical Stimulation to Speed Tendon Healing Researchers with the National University of Ireland Galway developed a device that assists tendon cell function and repair via electrical stimulation from an implantable device. In addition, the device is powered by body movement. The device uses a fabric-like mesh called piezoelectric material that generates electricity when stretched or placed under mechanical pressure. They can be tailored to individual patients or disorders. “Our discovery shows that an electrical charge is produced in the treatment target area — the damaged or injured tendon — when the implanted device is stretched during walking. The potential gamechanger here is like a power switch in a cell — the electrical stimulus turns on tendon-specific regenerative processes in the damaged tendon,” said Marc Fernandez, who carried out the principal research study at CURAM, the SFI Research Centre for Medical Devices based at NUI Galway. Identifying Proteins That Drive Glioblastoma Investigators at McGill University identified proteins that drive cancer stem cells, specifically galectin1. Glioblastoma is the most common and aggressive brain tumor in adults and is typically resistant to treatment. Surgery, radiation, and chemotherapy can ease symptoms for a few months, but the cancer cells usually regrow after treatment. The researchers found that by inhibiting the galectin1 protein, the brain tumors didn’t grow for several months. Galectin1 interacts with another protein, HOXA5, to control the pathways that drive cancer stem cell behavior. Suppressing galectin1 in preclinical models significantly improved tumor responses to radiation therapy and extended the lifespan of the animals they were working with. MMR and Tdap Vaccines Might Protect Against Severe COVID-19 A study out of Brigham and Women’s Hospital suggests that the childhood vaccines for Measles-Mumps-Rubella (MMR) and Tetanus-Diphtheria-Pertussis (Tdap) may prevent severe COVID-19. They theorize these vaccines might generate cross-reactive memory T cells that respond to antigens to a few microorganisms, including the viral antigens in SARS-CoV-2. They analyzed T cell responses to antigens from the blood of COVID-19 convalescent patients as well as patient vaccinated against COVID-19 and compared them to antigens from SARS-CoV-2 and the MMR and Tdap vaccines. Working with Cleveland Clinic, they pulled data from a cohort of COVID-19 patients that found previous MMR or Tdap vaccinated was linked to decreased disease severity. Patients previously vaccinated for MMR had a 38% decrease in hospitalization and a 32% decrease in ICU admission and death. Patients who received the Tdap had 23% and 20%, respectively, for hospitalization and ICU admission and death. “Our Cleveland Clinic colleagues observed an association where individuals with COVID-19 who had either MMR or Tdap vaccines had a much lower frequency of going to the intensive care unit or dying,” said co-author Andrew Lichtman, immunology and senior investigator in the Brigham and Women’s Hospital Department of Pathology and Professor of Pathology at Harvard Medical School. “Although previous smaller studies suggested a similar link, our in-depth epidemiological analyses, together with our basic research results, suggest that these commonly given vaccines may protect against severe disease.”

eQcell Inc. announces the initiation of two blinded, randomized trials in equine osteoarthritis at the University of Guelph’s Ontario Veterinary College Equine Sports Medicine and Reproductive Centre as well as at the University of California, Davis Veterinary Institute for Regenerative Cures (VIRC). The Canadian study in equine fetlock and in carpal joint osteoarthritis is authorized by Health Canada’s Veterinary Drug Directorate and it is the first stem cell trial in Canada for the treatment of equine osteoarthritis. The US study in fetlock osteoarthritis is conducted under VIRC’s Investigational New Animal Drug (INAD) with the FDA. The investigative drug is designed to provide safe, consistent, long-term joint pain management and, importantly, slow the degenerative structural changes within the joint, prolonging the time horses can compete or be ridden. The extension to human drug development is consistent with One Health* principles that innovative cell therapy development for humans is advantaged by initiating clinical trials in genetically-diverse companion and sporting animals in contrast to purpose-bred, genetically-homogenic laboratory animals. eQcell’s trials are structured to develop data in large animals both for rapid access to commercialization in the international veterinary markets, and to inform its longer-dated human clinical trials. eQcell’s approach to the human drug indication is novel and significant since confirmation of large-animal efficacy holds the financially-important prospect of reducing late-stage failures in human trials, while generating early revenues from commercialization in rapidlyapprovable veterinary applications. The protocols for these proof-of-concept trials in osteoarthritis, a common and widespread condition for which there is no joint-tissue preserving, or disease-slowing solution for either humans or animals, were designed by a consortium of world leaders in human and veterinary stem cell biology, and in equine sports medicine: • Dr. Frank Barry (Regenerative Medicine Institute, National University of Ireland Galway) • Dr. Larry Galuppo (Veterinary Institute for Regenerative Cures, UC Davis School of Veterinary Medicine) • Dr. Laurie Goodrich (Orthopaedic Research Center, Colorado State University's C. Wayne McIlwraith Translational Medicine Institute) • Dr. Scott Hopper (Rood & Riddle Equine Hospital, Kentucky) • Dr. Thomas Koch (Department of Biomedical Sciences, Ontario Veterinary College) • Dr. Judith Koenig (Equine Sports Medicine & Reproduction Centre, Ontario Veterinary College) The protocols for the two trials are designed to produce data to inform a pivotal trial to support initial marketing application in Europe due to EMA’s rapid regulatory pathway for equine drugs. European approval is planned to be followed by marketing applications in North America and internationally, and the data from the trials are designed to subsequently inform similar studies in humans and dogs. *US Centers for Disease Control & Prevention – Clinical trial information requests may be addressed to: Dr. Larry Galuppo – Veterinary Institute for Regenerative Cures, UC Davis ldgaluppo@ucdavis.edu Dr. Judith Koenig – Equine Sports Medicine & Reproduction Centre, Ontario Veterinary College jkoenig@uoguelph.ca