Category Archives: Cell Medicine

image:A breast cancer cell captured in the process of division, with tubulin (a structural protein) in red; mitochondria in green; and chromosomes in blue. view more

Credit: Wei QianNational Cancer Institute

Breast cancer and type 2 diabetes would seem to be distinctly different diseases, with commonality only in their commonality. Breast cancer is the second most diagnosed malignancy after some types of skin cancer; approximately 1 in eight U.S. women will develop invasive breast cancer over the course of their lifetime. More than 10 percent of the U.S. population has diabetes, with an estimated 2 in 5 Americans expected to develop the chronic disease during their lifetime.

However, past research has uncovered associations between the two diseases. Women with diabetes, for example, have a 20 to 27 percent increased risk of developing breast cancer. Insulin resistance a key characteristic of diabetes has been associated with breast cancer incidence and poor survival. Population studies suggest diabetes risk begins to increase two years after a breast cancer diagnosis, and by 10 years post-diagnosis, the risk is 20 percent higher in breast cancer survivors than in age-matched women without breast cancer.

But these epidemiological linkages are not clear-cut or definitive, and some studies have found no associations at all. In a new paper, publishing May 30, 2022 in Nature Cell Biology, a research team led by scientists at University of California San Diego School of Medicine describe a possible biological mechanism connecting the two diseases, in which breast cancer suppresses the production of insulin, resulting in diabetes, and the impairment of blood sugar control promotes tumor growth.

No disease is an island because no cell lives alone, said corresponding study author Shizhen Emily Wang, PhD, professor of pathology at UC San Diego School of Medicine. In this study, we describe how breast cancer cells impair the function of pancreatic islets to make them produce less insulin than needed, leading to higher blood glucose levels in breast cancer patients compared to females without cancer.

Wang said the study was inspired by early work and guidance from Jerrold Olefsky, MD, professor of medicine and associate dean for scientific affairs in the Division of Endocrinology and Metabolism at UC San Diego School of Medicine. Olefsky is co-senior author of the study with Wang.

The culprit, according to Wang and Olefsky, are extracellular vesicles (EV) hollow spheres secreted or shed by cells that transport DNA, RNA, proteins, fats and other materials between cells, a sort of cargo communication system.

In this case, the cancer cells were found to be secreting microRNA-122 into the vesicles. Wang said when vesicles reach the pancreas, they can enter the islet cells responsible for insulin production, dispense their miR-122 cargo and damage the islets critical function in maintaining a normal blood glucose level.

Cancer cells have a sweet tooth, Wang said. They use more glucose than healthy cells in order to fuel tumor growth, and this has been the basis for PET scans in cancer detection. By increasing blood glucose that can be easily used by cancer cells, breast tumors make their own favorite food and, meanwhile, deprive this essential nutrient from normal cells.

The research was conducted using mouse models, which found that slow-releasing insulin pellets or a glucose-lowering drug known as an SGLT2 inhibitor restored normal control of glucose in the presence of a breast tumor, which in turn suppressed the tumors growth.

These miR-122 inhibitors, which happen to be the first miRNA-based drugs to enter clinical trials, might have a new use in breast cancer therapy, Wang said.

Co-authors include: Minghui Cao, Roi Isaac, Wei Yan, Xianhui Ruan, Li Jiang, Yuhao Wan, Jessica Wang, Christine Caron, Donald P. Pizzo, Xuxiang Liu, Andrew R. Chin, Miranda Y. Fong, Oluwole Fadare, Richard B. Schwab, Wei Ying and Jack D. Bui, all at UC San Diego; Dorothy D. Sears, Arizona State University; Steven Neben and Denis Drygin, Regulus Therapeutics, Inc., San Diego; Xiwei Wu, Joanne Mortimer, Yuan Yuan and Susan E. Yost, all at City of Hope, Duarte, CA; Ziting Gao, Kaizhu Guo and Wenwan Zhong, all at UC Riverside.

# # #

Nature Cell Biology

30-May-2022

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The paired perils of breast cancer and diabetes - EurekAlert

A new study led by Hospital for Special Surgery (HSS) investigators in New York City has found that their computer vision tool effectively distinguishes rheumatoid arthritis (RA) from osteoarthritis (OA) in joint tissue taken from patients who underwent total knee replacement (TKR). The results suggest the machine learning model will help improve research processes in the short term and optimize patient care in the future. The findings were presented today at the European Alliance of Associations for Rheumatology (EULAR) Congress 2022.

TKR is often the only management option for patients with severe knee joint damage. Identifying which disease caused the joint damage is essential for guiding treatment plans, given that RA is a systemic, inflammatory disease that may also affect the eyes or lining around the heart, while OA affects just the joints. We know there are many more immune cells present in the synovium, or joint tissue, of patients with RA compared to those with OA, said Bella Mehta, MBBS, MS, rheumatologist at HSS and lead author of the study. But precisely how many more has not been clear.

Pathologists typically assess images of synovium to determine the extent of inflammation using a combination of approaches, including assigning the level of immune cell infiltration on a scale from 0 to 4, said Dana Orange, MD, MS, rheumatologist at HSS, assistant professor at Rockefeller University and senior author of the study. However, these methods are imperfect. For example, a recent study by HSS investigators found that assessments from two highly experienced pathologists evaluating the infiltration of one type of immune cells known as lymphocytes on the same slides agreed only 67 percent of the time.1

Drs. Orange, Mehta and colleagues at HSS and collaborating institutions developed and validated a computer vision tool that rapidly counts tens of thousands of cell nuclei in whole-slide images of synovium.2 For their present study, they measured 14 different pathologist-scored features in synovium from 60 patients with RA and 147 patients with OA who underwent TKR, and used the computer vision tool to determine cell density.

The investigators identified significant differences between RA and OA features in synovium. The RA samples showed increased cell density; low numbers of mast cells, a type of white blood cell; and lower evidence of fibrosis or scarring compared to the OA samples. The probability of correctly distinguishing between RA and OA in synovium was 85 percent when using the 14 pathologist-scored features alone, 88 percent when using the computers score for cell density alone and 91 percent when the researchers combined the pathologists scores and the computers cell density calculation. The researchers determined a cutoff point for distinguishing RA from OA, determining that synovium containing more than 3,400 cells per mm2 should be classified as RA.

While our innovation is not ready for clinical use yet, it holds promise for assisting pathologists in the future, Dr. Orange said. Right now, we see it as a valuable tool for research purposes because it provides an accurate and 100% reproducible score of inflammation and look forward to developing it further.

Dr. Orange added that in the future computer vision could be trained to glean other types of information from tissue samples, including which types of cells are present and whether they are close enough together that they are likely to be communicating with each other. This more granular assessment might enable clinicians to know more precisely which cells are causing tissue damage and tailor treatments accordingly.

Authors: Bella Mehta, MBBS, MS, Susan M. Goodman, MD, Edward F. DiCarlo, MD, Deanna Jannat-Khah, J. Alex Gibbons, Miguel Otero, PhD, Laura Donlin, PhD (HSS), Tania Pannellini, MD, PhD (Weill Cornell Medicine), William Robinson, MD, PhD (Stanford University), Peter K. Sculco, MD, Mark P. Figgie, MD, Jose A. Rodriguez, MD (HSS), Jessica Kirschmann (Stanford University), James Thompson, David Slater, Damon Frezza (The MITRE Corporation), Zhenxing Xu, Fei Wang, PhD (Weill Cornell Medicine), Dana Orange, MD, MS (HSS and Rockefeller University).

References

1. Orange DE, Agius P, DiCarlo EF, et al. Identification of Three Rheumatoid Arthritis Disease Subtypes by Machine Learning Integration of Synovial Histologic Features and RNA Sequencing Data.Arthritis Rheumatol. 2018;70(5):690-701. doi:10.1002/art.40428

2. Guan S, Mehta B, Slater D, et al. Rheumatoid Arthritis Synovial Inflammation Quantification Using Computer Vision.ACR Open Rheumatol. 2022;4(4):322-331. doi:10.1002/acr2.11381

About HSS

HSS is the worlds leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 12th consecutive year), No. 4in rheumatology by U.S. News & World Report (2021-2022), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report Best Childrens Hospitals list (2021-2022).In a survey of medical professionals in more than 20 countries by Newsweek, HSS is ranked world #1 in orthopedics for a second consecutive year (2022). Founded in 1863, the Hospital has the lowest complication and readmission rates in the nation for orthopedics, and among the lowest infection rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center five consecutive times. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. The HSS Innovation Institute works to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 145 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally.www.hss.edu.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Computer vision tool improves the ability to distinguish rheumatoid arthritis from osteoarthritis in damaged joint tissue - EurekAlert

Immunotherapy unleashes the power of the immune system to fight cancer. However, for some patients, immunotherapy doesnt work, and new research may help explain why. When immune cells called T lymphocytes infiltrate malignant tumors, the genetic program of those T cells and the developmental path they then follow, may affect their response to immunotherapy and predict overall patient survival, according to a new study by Weill Cornell Medicine investigators. The results overturn the prevailing model of immune responses in melanoma and present different therapeutic approaches.

In the study, published May 9 in Cancer Cell, the investigators analyzed thousands of human tumor samples, plus individual human T cells across many data sets and tumor types, and compared these to many models of T cell behavior in response to infections, cancer and vaccines, including human vaccines. They found that T cells either become stuck in an early activation state or develop into memory cells that are expanded by current immunotherapy approaches.

The T cells dont behave in a singular manner, but we can understand their behavior and model it in a way that can predict patient outcomes and overall survival, said senior author Dr. Niroshana Anandasabapathy, associate professor of dermatology and of dermatology in microbiology and immunology at Weill Cornell Medicine, and a practicing dermatologist for melanoma patients at NewYork-Presbyterian/Weill Cornell Medical Center.

Scientists have long known that the immune system can detect and eliminate tumor cells on its own, but this process sometimes breaks down, leading to the development of cancer. Previous data seemed to support a theory in which, once a tumor is established, T lymphocytes entering the tumor keep seeing and responding to tumor proteins until they become exhausted and unable to attack the cancerous cells. That theory was used to explain the success of a type of therapy called immune checkpoint blockade, which uses cellular signals to improve T cell responses, reawakening the T cells ability to attack and eliminate the tumor.

Some patients tumors dont respond to immune checkpoint blockade, though. To figure out why, the team began looking at larger data sets and analyzing them more broadly than previous studies.

We wanted to take an entirely agnostic approach to trying to understand what happens to a T cell when it enters the tumor microenvironmenta really naive, unbiased approach, said Dr. Anandasabapathy, who is also a member of the Sandra and Edward Meyer Cancer Center and the Englander Institute for Precision Medicine.

By using large programs of many genetic markers and multiple, simultaneous genomic strategies to categorize cell fates, Dr. Anandasabapathy and her collaborators were able to re-classify T cells in tumors, and better model how they develop. The results show that infiltrating T cells dont all meet the same fate in every tumor. In contrast to the standard view, a failure to launch beyond early activation and convert to memory, and not exhaustion appeared to be the problem. The enrichment of long-lived memory programs correlates strongly with overall survival and a successful response to immune checkpoint blockade therapy in melanoma.

In addition to predicting outcomes, the investigators hope to find ways to change them. Getting T cells past their failure to launch and inducing the formation of tumor-infiltrating memory T cells in patients who lack them, for example, could make non-responsive tumors sensitive to immune checkpoint blockade.

While the current work focused on malignant melanoma, the scientists also identified that similar phenomena likely underlie differences in patient T cell responses to other types of cancer, including kidney, bladder, prostate and liver cancer.

The power of the study is really in opening new avenues of discovery and suggesting more rational therapeutics, said first author Abhinav Jaiswal, a doctoral candidate at Weill Cornell Graduate School of Medical Sciences in Dr. Anandasabapathys laboratory.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosurespublic to ensure transparency. For this information, see profile for Dr. Niroshana Anandasabapathy.

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T Cell Behavior Determines Which Tumors Respond to Treatment - Weill Cornell Medicine Newsroom

Astrocytes make up almost half of the mammalian brain cells. They are called glial cells because scientists originally thought that these starlight-shaped structures serve as nerve glue.

Research suggests that these cells control the growth of axons, or the neuronal projections that carry electrical impulses.

However, scientists still considered astrocytes to be supporting actors behind neurons, which are the primary cells of the brain and nervous system.

Now, scientists at Tufts University in Massachusetts and other institutions realize that astrocytes may execute a significantly greater performance in brain activity.

Dr. Moritz Armbruster, a research assistant professor of neuroscience at Tufts, led a team of researchers in harnessing novel technology to study astrocyte-neuron exchanges.

To their surprise, the scientists observed electrical activity in astrocyte processes within mouse brain tissue. They reported: This represents a novel class of subcellular astrocyte membrane dynamics and a new form of astrocyteneuron interaction.

Dr. Armbruster and his fellow authors published their findings in Nature Neuroscience.

Using innovative tools, the Tufts team developed a technique to detect and observe electrical activity in brain cell interactions. These properties could not be seen before now.

Dr. Chris Dulla, corresponding author of the study, is an associate professor of neuroscience at the Tufts University School of Medicine and Graduate School of Biomedical Sciences. He explained that he and his colleagues []use viruses to express fluorescent proteins in the mouse brain, and thats what lets us measure this activity.

In an interview with Medical News Today, he elaborated:

[W]e had other experiments that made us think that this new type of activity must be happening in astrocytes. We just didnt have a way to show it[] So, we developed these new techniques to image the activity of the astrocytes and, using them, we showed that this thing that we thought must be happening actually was happening.

Neurotransmitters are chemical messengers that facilitate the transfer of electrical signals between neurons and support the blood-brain barrier. Scientists have long understood that astrocytes control these substances to support neuronal health.

This study breaks ground in showing that neurons release potassium ions, which change the astrocytes electrical activity. This modulation affects how the astrocytes control neurotransmitters.

Until now, scientists could not image potassium activity in the brain.

Neurons and astrocytes talk with each other in a way that has not been known about before, Dr. Dulla said.

Dr. Dulla maintains that human brain cells work the same way as mouse tissue. He said that mouse and human brain cells use the same proteins and molecules involved in brain activity.

Besides, using human tissue samples presents ethical challenges, Dr. Dulla noted: [We] have to be really careful and judicious [] with the experiments we design, and [we] dont get a chance to see [human tissue] samples like [we] can do with mice.

However, the professor shared that extensive databases give [scientists] a chance to just access human brain tissue without doing an experiment [themselves], but just getting the data that someone else has already done.

This wealth of information further demonstrates similarities between human and mouse cells and lets researchers deduce that the same processes are happening in each. The main difference is that human cells are larger and more abundant.

He also pointed out that the study highlights a bidirectional relationship between these brain cells, as astrocytes influence the neurons as well.

These findings about astrocyte-neuron interactions open a new world of questions regarding brain pathology, memory, and learning.

MNT also discussed this study with Dr. Santosh Kesari, who was not involved in this research. He is a neurologist at Providence Saint Johns Health Center in Santa Monica, CA, and regional medical director for the Research Clinical Institute of Providence Southern California.

Dr. Kesari said that this study confirms earlier research.

[T]his is one of many studies thats showing increasingly, how astrocytes and neurons interact, how they affect each other and then connecting the dots to how that affects brain function behavior, memory, seizures, dementia, and even in the context of brain tumors, all these cells interact. Dr. Santosh Kesari

Most medication development for brain disorders currently targets neurons. Dr. Kesari agreed that this study might shine light on a new path.

Maybe we should really be understanding the astrocyte side of things to develop drugs that may impact brain health by looking at that astrocytic role in brain disorders, he said.

The ability to image cell processes, as in this study, makes it possible to explore other activities within the brain as well.

The researchers are also screening existing drugs in hopes of manipulating astrocyte-neuron processes. Scientists could come close to repairing brain injuries or helping people increase their learning capacity if this proves successful.

They are also making their tools available to other labs to explore more areas of interest, such as breathing, headache, and many other neurological disorders.

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Researchers find new function performed by almost half of brain cells - Medical News Today

DUBLIN--(BUSINESS WIRE)--The "Regenerative Medicine Market by Product Type, Material, Application and End user (Hospitals, Ambulatory Surgical Centers, and Others: Global Opportunity Analysis and Industry Forecast, 2021-2030" report has been added to ResearchAndMarkets.com's offering.

The regenerative medicine market size was valued at $10,107.32 million in 2020, and is estimated to reach $83,196.72 million by 2030, growing at a CAGR of 23.4% from 2021 to 2030.

Regenerative medicine is a process of replacing human cells, tissues or organs to restore or establish normal function. It is field that brings together experts in biology, chemistry, genetics and medicine. This is a promising field which working to restore structure and function of damaged tissues and organs.

It includes cell therapy involves the use of cellular materials such as stem cells, autologous cells, xenogeneic cells, and others, for the therapeutic treatment of patients. Cell therapy is used to replace damaged cells, deliver therapies to target tissues/organs, stimulate self-healing, and various other applications in regenerative medicine.

The major factors boosting the regenerative medicine market growth include technological advancements in tissue and organ regeneration, increase in prevalence of chronic diseases and trauma emergencies, prominent potential of nanotechnology, and emergence of stem cell technology.

In addition, increase in incidence of degenerative diseases and shortage of organs for transplantation are expected to boost the growth of the market. The prominent potential of regenerative medicine to replace, repair, and regenerate damaged tissues and organs has fueled the market growth. In addition, technological advancements in regenerative medicine production and advancement in the stem cell therapy procedures propel the growth of the market.

Rise in prevalence of musculoskeletal diseases and increase in dermatological treatments propel the growth of the market. Moreover, utilization of nanomaterial's in wound care, drug delivery, and immunomodulation has opened growth avenues for the regenerative medicine market.

However, stringent regulations, operational inefficiency, and high cost of regenerative medicine treatment are key factors that hinder the market growth. Furthermore, advancements in stem cell technology and increase in R&D activities in the emerging economies are expected to fuel the market growth during the forecast period. Developed nations have adopted technological advancements in tissue engineering and regenerative medicine sectors, which help in the expansion of the global market.

Moreover, rise in development of pharmaceutical and medical device industries and improvement in healthcare spending are anticipated to drive the growth of the regenerative medicine market. In addition, increase in demand for regenerative medicine led to development of innovative technologies in the healthcare sector, thereby propelling growth of the market.

Moreover, initiatives taken by governments for development of advanced stem cell therapies and development of the healthcare sector for manufacturing of regenerative medicine are the key factors that boost growth of the market. Furthermore, surge in geriatric population, who are more vulnerable to chronic disease, propels the market growth.

KEY MARKET PLAYERS

KEY MARKET SEGMENTS

By Product Type

By Material

By Application

By End User

By Region

For more information about this report visit https://www.researchandmarkets.com/r/qek5u

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$83 Bn Regenerative Medicine Markets - Global Opportunity Analysis and Industry Forecast, 2021-2022 & 2030 - ResearchAndMarkets.com - Business...

Dr. Melody Zeng, an assistant professor of immunology in pediatrics and a member of the Gale and Ira Drukier Institute for Childrens Research at Weill Cornell Medicine, has received a 2021 Hartwell Individual Biomedical Research Award from The Hartwell Foundation. The award provides support for three years at $100,000 direct cost per year and designation as a Hartwell Investigator.

Dr. Zengs award will support her research into the connection between gut bacteria in infants and an increased risk of developing autism spectrum disorder (ASD) after exposure to maternal antidepressants. The incidence of ASD continues to rise, with the latest estimates showing about 1 in 44 children have been identified with ASD by the age of eight years, according to the Centers for Disease Control and Prevention. ASD causes differences in the brain and typically begins before the age of 3. Patients experience a wide variety and severity of symptoms, which may include problems with social interaction and communication, repetitive behaviors, different ways of moving or paying attention and intellectual disability.

I am excited and honored to receive a Hartwell Award, as it will be instrumental in advancing my early-stage research, Dr. Zeng said. Ultimately, I hope new understandings of the link between gut bacteria and an increased risk of ASD in infants exposed to maternal antidepressants may help us identify potential treatment targets for reversing the adverse effects and lowering the risk for children.

Scientists believe multiple factors contribute to the development of ASD. Recent studies have found a link between gut bacteria and ASD onset, but the underlying mechanisms are not well understood. Evidence has shown that more than 25 percent of children identified with ASD have high blood levels of serotonin, a chemical transmitter produced by gut bacteria in the intestine that plays a role insignal transmission between nerve cells throughout the brain and body. Previously, serotonin production processes were assumed to be the same in adults and babies. Dr. Zeng is among the first researchers to show that babies have much higher serotonin levels in their stool during early developmental stages than adults.

Antidepressants aim to alleviate depression and anxiety by raising serotonin levels in the brain. Their use has greatly increased during pregnancy over the last few decades, and there appears to be a link to ASD. Reports show that infants of mothers who took antidepressants during pregnancy or while breastfeeding had a 60 percent greater risk of developing ASD than infants whose mothers did not take the medications.

Based on our preliminary findings, we think that maternal antidepressant use during pregnancy and breastfeeding may alter the levels of serotonin in infants, potentially leading to brain inflammation and an increased risk of ASD onset, said Dr. Zeng. She and her team will investigate how gut bacteria control serotonin production processes using human infant stool samples and mouse models of maternal antidepressant use. Dr. Zeng has been building a biobank of human neonatal stool samples from infants admitted to the Neonatal Intensive Care Unit or the Well-Baby Nursery at NewYork-Presbyterian/Weill Cornell Medical Center in collaboration with Dr. Jeffrey Perlman, professor of pediatrics at Weill Cornell Medicine. Dr. Zeng is also collaborating with Dr. Virginia Pascual, the Drukier Director of the Drukier Institute for Childrens Health at Weill Cornell Medicine, on using single-cell RNA sequencing to analyze immune cells in the brains of mice transplanted with stool bacteria from infants that have and have not been exposed to maternal antidepressants.

The Hartwell Foundation has funded early-stage biomedical research with the potential to benefit children in the United States since 2006. Hartwell Individual Biomedical Research Awards are awarded annually to a limited number of researchers conducting early-stage, cutting-edge research with the potential to benefit the health of American children and have not yet been funded by other sources. Dr. Zeng is one of 10 awardees selected from eight institutions by the Hartwell Foundation in 2021.

Dr. Zengs Individual Biomedical Research Award qualifies Weill Cornell Medicine to designate a Hartwell Fellowship to fund one postdoctoral candidate in an early stage of their career. The fellowship funded by The Hartwell Foundation provides $50,000 direct cost per year for two years in support of specialized training in biomedical research.

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Dr. Melody Zeng Receives a Hartwell Foundation Individual Biomedical Research Award - Weill Cornell Medicine Newsroom

A second line of defense the immune systems T cells may offer protection from COVID-19 even when vaccine-induced antibodies no longer can, according to new research out of the University of Wisconsin School of Veterinary Medicine.

The researchers discovered that a new, protein-based vaccine against the original version of the COVID-19 virus was able to teach mouse T cells how to recognize and kill cells infected with new, mutated versions of the virus. This T cell protection worked even when antibodies lost their ability to recognize and neutralize mutated SARS-CoV-2, the virus that causes COVID-19.

Marulasiddappa Suresh

Antibodies prevent COVID-19 infection, but if new variants escape these antibodies, T cells are there to provide a second line of protection, explains lead scientist Marulasiddappa Suresh, a professor of immunology and associate dean for research at the School of Veterinary Medicine.

The study, published in the Proceedings of the National Academy of Sciences on May 13, investigates the role of T cells, a specialized type of white blood cell, in defending against COVID-19 when antibodies fail.

When you receive a COVID-19 vaccine, your body learns to produce antibodies, proteins in the immune system that bind to and neutralize SARS-CoV-2. These antibodies circulate in the blood stream and protect you from illness by patrolling the nostrils, airways and lungs and wiping out the virus before it can cause infection or disease.

However, as SARS-CoV-2 mutates, these highly specific antibodies are less able to recognize new viral variants especially if the changes occur on the viruss spike protein, where the vaccines antibodies bind. This was especially apparent during the recent wave of the SARS-CoV-2 omicron variant, which has a staggering 37 mutations on its spike protein, making it more able to evade antibodies targeting the original viruss spike protein.

The biggest problem right now is that none of our current COVID-19 vaccines give complete protection against infection from emerging variants, especially the omicron sublineages BA.1 and BA.2, Suresh says.

Thats where T cells can help. Killer T cells aid the immune system by hunting and eliminating virus factories infected cells, says Suresh. So, when antibodies cannot neutralize the virus prior to infection, T cells can clear it quickly, causing mild or no noticeable symptoms.

With this information in hand, the UWMadison research team, co-led by Suresh and professor of pathobiological sciences Jorge Osorio and assisted by scientist Brock Kingstad-Bakke and doctoral student Woojong Lee, explored how T cells and antibodies can work to prevent COVID-19 infection altogether.

Brock Kingstad-Bakke, a scientist in the UW School of Veterinary Medicine. Photo courtesy of the School of Veterinary Medicine

The researchers developed an experimental protein-based vaccine containing the unmutated version of the spike protein from the original SARS-CoV-2 virus. This vaccine was also designed to elicit a strong T cell response to the viral spike protein, allowing the lab to test the extent to which T cells can protect against COVID-19 infection in the presence and absence of virus neutralizing antibodies.

After injecting mice models with their vaccine, researchers then exposed them to two SARS-CoV-2 variants and tested their susceptibility to infection under different conditions.

While vaccine-stimulated antibodies were unable to neutralize the mutated SARS-CoV-2 variants, mice were still immune to COVID-19 caused by the mutated viruses, due to action by T cells that were induced by the vaccine.

Unlike antibodies, T cells are able to detect unfamiliar strains of virus because the viral fragment that they recognize does not change considerably from one variant to the next.

This work has important implications for future T cell-based vaccines that could provide broad protection against emerging SARS-CoV-2 variants. The experimental vaccine is protein-based and designed to evoke a strong T cell response, differentiating it from currently available mRNA vaccines.

Now, the Suresh lab is studying how exactly T cells defend against SARS-CoV-2 and whether commercially available COVID-19 vaccines may induce these same mechanisms of T cell immunity to protect against emerging variants when the virus dodges established antibodies.

I see the next generation of vaccines being able to provide immunity to current and future COVID-19 variants by stimulating both broadly-neutralizing antibodies and T cell immunity, Suresh says.

This work was supported in part by the National Institutes of Health (grants U01 AI124299, R21 AI149793-01A1).

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Experimental COVID-19 vaccine provides mutation-resistant T cell protection in mice - University of Wisconsin-Madison

UNC-Chapel Hill scientists led by Mark Zylka, PhD, found measurable levels of a biomarker for azoxystrobin in pregnant women and young kids, and investigated the fungicides ability to pass from mothers to embryos in utero in mice and during lactation.

CHAPEL HILL, NC For the first time, UNC-Chapel Hill researchers have measured the concentration of a biomarker of the commonly used fungicide azoxystrobin (AZ) in the urine of pregnant women and children ranging from 40-84 months of age. They also documented maternal transfer of AZ to mouse embryos and weaning-age mice.

The researchers experimental data, published in the journal Environmental Health Perspectives, also found that AZ entered the brain of mice in utero at concentrations that modeled environmentally relevant exposures. Using similar concentrations, the researchers then found that AZ killed some embryonic cortical neurons in cultures.

The most concerning aspect of our research is that this fungicide is now widely being used in certain brands of mold-resistant wallboards, said senior author Mark Zylka, PhD, director of the UNC Neuroscience Center. Our study shows that pregnant women and children are exposed to azoxystrobin at much higher levels than expected from food sources alone.

Zylka, who is the W.R. Kenan Distinguished Professor of Cell Biology and Physiology at the UNC School of Medicine, began studying the effects of this fungicide on brain cells several years ago when he and colleagues found that members of this fungicide class caused gene expression changes that are indicative of brain inflammation, a process seen in individuals with autism and age-related cognitive conditions.

These chemicals stimulate free radical production and disrupt microtubules parts of neurons important for cell division, the transport of chemicals between cells, and the maintenance of cell shape.

The agricultural industry began using AZ and related strobilurin-class fungicides in the mid-1990s, and usage has increased exponentially to 1,000 tons applied to vegetable, nut, potato, fruit and grapevine crops in the United States, as well as to cereals and turf grass. AZ has been found in large amounts in surface water due to agricultural runoff. It is known to be harmful to aquatic life and invertebrates.

Later, AZ was added to specific brands of mold and mildew-resistant wallboards, now commonly used in residential and commercial construction.

In the past decade, several experimental studies found AZ has the potential to cause developmental toxicity and neurotoxicity. In cortical neuron cultures prepared from embryonic mice, AZ induced reactive oxygen species (free radicals) that can damage cells. In zebrafish, AZ altered cell death-related gene expression in larvae and caused oxidative stress in larvae and in adults. Following parental AZ exposure in zebrafish, a significantly higher incidence of mortality and malformations was observed in offspring.

These studies suggested that AZ is toxic at embryonic stages, and as a result of these studies, scientists identified it as a major front-line target chemical for biomonitoring in the United States. Yet, there isnt much information about whether humans especially young children and pregnant mothers are exposed to detrimental amounts of AZ, or whether the fungicide can be transferred from mother to embryos, and if so, what are the health ramifications.

Zylkas lab conducted experiments, led by first author Wenxin Hu, PhD, a UNC-Chapel Hill postdoctoral researcher, to measure the concentration of a biomarker of AZ exposure (AZ-acid) in the urine of pregnant women and in a separate group of children ranging from 40 to 84 months old. AZ-acid was present in 100% of the urine samples from pregnant women and in 70% of the urine samples from children, with median concentration of 0.10 and 0.07 ng/mL (nanograms per milliliter) and max concentration of 2.70 and 6.32 ng/mL, respectively.

Experiments further revealed that AZ crossed the placenta and entered the developing brain of mouse embryos, and AZ transferred to offspring during lactation.

Azoxystrobin has been detected in house dust, with some samples showing high concentrations, Zylka said. Our current research shows that azoxystrobin is being metabolized by humans, which means humans are ingesting it. Some of the children had persistently high levels of the metabolite, suggesting they are chronically exposed to azoxystrobin. This fungicide is on-track to become as prevalent in the home as other chemicals like pyrethroids, plasticizers, and flame retardants. We urge the scientific community to ramp up efforts and determine if chronic exposure to azoxystrobin affects humans during fetal development and after birth.

Other authors of this paper are Chih-Wei Liu, Yun-Chung Hsiao, Kun Lu in the UNC Department of Environmental Health Sciences at the UNC Gillings School of Global Public Health; JessicaA. Jimnez in the Curriculum in Toxicology & Environmental Medicine; Eric S. McCoy at the UNC Neuroscience Center the UNC Department of Cell Biology and Physiology; Weili Lin, director of the UNC Biomedical Research Imaging Center and the UNC Department of Radiology in the UNC School of Medicine; and Stephanie M. Engel in the UNC Department of Epidemiology at Gillings.

Funding for this research came from the Simons Foundation, The National Institute of Environmental Health Sciences (NIEHS, R35ES028366; P30 ES010126), the National Institute of Mental Health (U01MH110274), and a Gillings Innovation Laboratory award from the UNC Gillings School of Global Public Health.

Environmental Health Perspectives published this companion piece to the peer-reviewed scientific paper led by the Zylka lab.

Media contact: Mark Derewicz, mark.derewicz@unchealth.unc.edu

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Scientists Detect Common Fungicide in Pregnant Women and Children | Newsroom - UNC Health and UNC School of Medicine

Distinct genetic variants significantly influence an individual's immune response to the SARS-CoV-2 virus and may influence the COVID-19 disease severity. A research group led by MedUni Vienna was able to demonstrate that distinct genetic variants of the CD16a antibody receptor are associated with the risk of severe COVID-19. This affects around 15% of the population. The results were now published in the journal "Genetics in Medicine".

Natural killer cells (NK cells) play a significant role in combating the viral replication in the initial stages of viral infections. NK cells have specialized receptors on their surface that bind to antibodies that are specifically produced against viruses. This enables the antibody-dependent activation of killer cells (ADCC), which leads to the destruction of virus-infected cells and triggers the release of pro-inflammatory factors.

This interaction between antibodies and the NK cell surface receptor is influenced by certain genetic factors, resulting in either strongly (high-affinity) or weakly (low-affinity) binding genetic receptor variants. Working in collaboration with Alexander Zoufaly from the Favoriten hospital, a research group led by Hannes Vietzen and Elisabeth Puchhammer-Stckl from the Center for Virology of the Medical University of Vienna has now shown that certain genetic variants of the CD16a antibody receptor are associated with the risk of severe COVID-19.

In their study, recently published in the journal "Genetics in Medicine", the authors show that people who had to be hospitalized with severe COVID-19 were significantly more likely to have the high-affinity variant of the CD16a receptor. This high-affinity variant only occurs in around 15% of the population, and carriers of this variant have a significantly higher risk of developing severe COVID-19. This high-affinity variant was particularly common in COVID-19 patients who had to be treated in intensive care units or who died from COVID-19.

In subsequent cell culture experiments, the research team was able to show that this high-affinity variant of the antibody receptor results in a significantly elevated antibody-dependent activation of NK cells and in a particularly strong release of pro-inflammatory factors.

Hannes Vietzen explains: "The antibody-dependent activation of NK cells is a delayed immune response. It now appears that this particular immune response no longer helps to control the SARS-CoV-2 viral replication but aggravates the course of COVID-19 disease by triggering an exaggerated immune response."

The tests involved are special scientific assays. Routine laboratory testing for these parameters is not being considered, since there are currently no therapeutic or preventive options targeting this genetic predisposition to reduce the risk of severe COVID-19. Genetic predisposition is further only one of several factors that influence the severity of the disease.

Genetics in Medicine

High-affinity FcRIIIa genetic variants and potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) responses contributing to severe COVID-19

30-Apr-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Distinct cellular receptor mutations influence the COVID-19 disease severity - EurekAlert

Restoring lost gene activity prevents many disease signs in an animal model of the rare, single-gene neurodevelopmental condition. The UNC Neuroscience Center lab of Ben Philpot, PhD, led this research.

CHAPEL HILL, NC UNC School of Medicine Scientists have shown for the first time that postnatal gene therapy may be able to prevent or reverse many deleterious effects of a rare genetic disorder called Pitt-Hopkins syndrome. This autism spectrum disorder features severe developmental delay, intellectual disability, breathing and movement abnormalities, anxiety, epilepsy, and mild but distinctive facial abnormalities.

The scientists, who report their results in the journal eLife, devised an experimental, gene-therapy-like technique to restore the normal activity of the gene deficient in people with Pitt-Hopkins syndrome. In newborn mice that otherwise model the syndrome, the treatment prevented the emergence of disease signs including anxiety-like behavior, memory problems, and abnormal gene expression patterns in affected brain cells.

This first, proof-of-principle demonstration suggests that restoring normal levels of the Pitt-Hopkins syndrome gene is a viable therapy for Pitt-Hopkins syndrome, which otherwise has no specific treatment, said senior author Ben Philpot, PhD, Kenan Distinguished Professor of Cell Biology and Physiology at the UNC School of Medicine and associate director of the UNC Neuroscience Center.

Most genes are inherited in pairs, one copy from the mother and one from the father. Pitt-Hopkins syndrome arises in a child when one copy of the gene TCF4 is missing or mutated, resulting in an insufficient level of TCF4 protein. Typically, this deletion or mutation occurs spontaneously in the parental egg or sperm cell prior to conception, or in the earliest stages of embryonic life following conception.

Only about 500 cases of the syndrome have been reported worldwide since it was first described by Australian researchers in 1978. But no one knows the syndromes true prevalence; some estimates suggest that there could be more than 10,000 cases in the United States alone.

Since TCF4 is a transcription factor gene, a master switch that controls the activities of at least hundreds of other genes, its disruption from the start of development leads to numerous developmental abnormalities. In principle, preventing those abnormalities by restoring normal TCF4 expression as early as possible is the best treatment strategy but it hasnt yet been tested.

Philpots team, led by first author Hyojin (Sally) Kim, PhD, a graduate student in the Philpot lab during the study, developed a mouse model of Pitt-Hopkins syndrome in which the level of the mouse version of TCF4 could be reliably halved. This mouse model showed many typical signs of the disorder. Restoring full activity of the gene from the start of embryonic life fully prevented these signs. The researchers also found evidence in these initial experiments that gene activity needed to be restored in essentially all types of neurons to prevent the emergence of Pitt-Hopkins signs.

The researchers next set up a proof-of-concept experiment modeling a real-world gene therapy strategy. In engineered mice in which roughly half the expression of the mouse version of Tcf4 was switched off, the researchers used a virus-delivered enzyme to switch the missing expression back on again in neurons, just after the mice were born. Analyses of the brains showed this restoration of activity over the next several weeks.

Even though the treated mice had moderately smaller brains and bodies compared to normal mice, they did not develop many of the abnormal behaviors seen in untreated Pitt-Hopkins model mice. The exception was innate nest-building behavior, in which the treated mice seemed abnormal at first, although their abilities were restored to normal within a few weeks.

The treatment at least partly reversed two other abnormalities seen in untreated mice: altered levels of the genes regulated by TCF4 and altered patterns of neuronal activity as measured in electroencephalograph (EEG) recordings.

These findings offer hope that a future gene therapy will provide significant benefits to individuals with Pitt-Hopkins syndrome even when delivered postnatally; it wont require diagnosis and treatment in utero, Kim said.

Philpot and his lab now plan to explore the effectiveness of their strategy when applied to Pitt-Hopkins mice at later stages of life. They also plan to develop an experimental gene therapy in which the human TCF4 gene itself will be delivered by a virus into a Pitt-Hopkins mouse model a therapy that ultimately could be tested in children with Pitt-Hopkins syndrome.

Well be working on a gene therapy, but our results here suggest that there are other TCF4-restoring approaches that could work, including treatments that boost the activity of the remaining, good TCF4 copy, Philpot said.

The research was supported by the Ann D. Bornstein Grant from the Pitt-Hopkins Research Foundation, the National Institute of Neurological Disorders and Stroke (R01NS114086), the Estonian Research Council, and the Orphan Disease Center at the Perelman School of Medicine at the University of Pennsylvania (MDBR-21-105-Pitt Hopkins).

The paper in eLife Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression was written by Hyojin (Sally) Kim, who is now a scientist at Life Edit Therapeutics, Eric Gao, Adam Draper, Noah Berens, Hanna Vihma, Xinyuan Zhang, Alexandra Higashi-Howard, Kimberly Ritola, Jeremy Simon, Andrew Kennedy, and Ben Philpot.

Media contact: Mark Derewicz, 919-923-0959

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Gene Therapy Could Treat Pitt-Hopkins Syndrome, Proof-of-Concept Study Suggests | Newsroom - UNC Health and UNC School of Medicine