Cell Biology

Study uncovers a unique, efficient method of copper delivery in cells – Phys.org

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A new study has uncovered a unique way in which the anti-cancer drug elesclomol enables copper delivery in cells, aiding in the search for treatments for copper deficiency disorders such as Menkes disease.

Menkes disease is an extremely rare hereditary copper-deficiency disorder in infants. It is characterized by progressive neurological injury culminating in death, typically by the age of three.

A Texas A&M AgriLife Research team led by Vishal Gohil, Ph.D., associate professor in the Department of Biochemistry and Biophysics in Texas A&M's College of Agriculture and Life Sciences, Bryan-College Station, first discovered the therapeutic potential of elesclomol for treating copper deficiency disorders. Additionally, previous research by Gohil's team showed that elesclomol could be used effectively in a mouse model to treat Menkes disease.

The new study, "FDX1-dependent and independent mechanisms of elesclomol-mediated intracellular copper delivery," was recently published in the Proceedings of the National Academy of Sciences, a peer-reviewed journal of the National Academy of Sciences. The research was led by Gohil, with Mohammed Zulkifli, Ph.D., a research scientist in the same department, as the first author of the study.

The study was conducted in collaboration with scientists from the University of Houston, Oregon Health and Science University, University of Missouri and the Advanced Photon Source at Argonne National Laboratory, a U.S. Department of Energy multidisciplinary science and engineering research center.

Genetic defects in copper transport to copper-containing enzymes, referred to as "cuproenzymes," result in fatal disorders such as Menkes disease. No effective treatment is currently available for these copper deficiency disorders.

"To realize the full potential of elesclomol, it was necessary to gain a mechanistic understanding of how this drug makes copper available to different cellular cuproenzymes," Gohil said. "We needed to look at the mechanism by which copper brought into cells by elesclomol is released and delivered to cuproenzymes present in different subcellular compartments."

He said the study used a combination of biochemistry, cell biology and genetics to demonstrate that the release of copper from elesclomol occurs both inside and outside mitochondria. Vishal Gohil, Ph.D., left, and Mohammad Zulkifli, Ph.D., right, in the Gohil Laboratory at Texas A&M University. Credit: Texas A&M AgriLife photo by Michael Miller

Copper is an essential trace element required for the activity and stability of several cuproenzymes involved in a wide array of physiological processes.

"Copper is an essential micronutrient, and genetic mutations that prevent copper transport across cellular membranes or its delivery to cuproenzymes can result in lethal human disorders such as Menkes disease," Gohil said.

Currently, no Food and Drug Administration-approved therapies are available for treating Menkes disease. Additionally, direct administration of hydrophilic copper salts has shown limited efficacy in clinical trials.

"We hypothesized that this limited efficacy was likely due to inefficient copper delivery across cellular membranes, so there was an unmet need to identify compounds that can safely and effectively transport copper across biological membranes and restore cellular copper balance," Gohil said.

Previous research had shown that ferredoxin 1, FDX1, a mitochondrial enzyme, was the protein target of elesclomol. In the current study, Gohil and his team showed that FDX1 releases copper bound to elesclomol by reducing it to a form of copper cells can use. The study also showed that even when FDX1 was absent, elesclomol could still bring some copper into cells in other unknown ways.

Zulkifli said FDX1 can also help release copper from other clinically used copper-transporting drugs, but compared with elesclomol, these drugs are much less dependent on FDX1 to make the copper bioavailable to cuproenzymes.

"These modes of copper release by elesclomol are distinct from those of other currently used copper-transporting drugs," Zulkifli said. "This may explain the high potency of elesclomol in rectifying copper deficiency."

Previous studies by Gohil and his team have highlighted the therapeutic potential of elesclomol in treating diseases of copper deficiency. Some of this previous research also showed that elesclomol can restore the levels of cytochrome c oxidase protein complex, a critical copper-dependent enzyme required for mitochondrial energy production.

The Gohil lab also demonstrated that elesclomol improves copper deficiency in yeast, zebrafish and mouse models by delivering copper to mitochondria and restoring the function of the cytochrome c oxidase.

Additionally, the use of elesclomol to treat copper deficiency disorders is at the center of a licensing agreement between The Texas A&M University System, managed through the Intellectual Property and Commercialization office of Texas A&M AgriLife Research, and California-based Engrail Therapeutics.

More information: Mohammad Zulkifli et al, FDX1-dependent and independent mechanisms of elesclomol-mediated intracellular copper delivery, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2216722120

Journal information: Proceedings of the National Academy of Sciences

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Study uncovers a unique, efficient method of copper delivery in cells - Phys.org

Cell Biology

Fooling Biology: Can Synthetic Polymers Replace the Body’s … – SciTechDaily

Biological fluids are made up of hundreds or thousands of different proteins (represented by space-filling models above) that evolved to work together efficiently but flexibly. UC Berkeley polymer scientists are trying to create artificial fluids composed of random heteropolymers (threads inside spheres) with much less complexity, but which mimic many of the properties of the natural proteins (right), such as stabilizing fragile molecular markers. Credit: Zhiyuan Ruan, Ting Xu lab, UC Berkeley

The majority of life on Earth relies on polymers made up of 20 different amino acids, which have evolved into hundreds of thousands of specialized proteins. These proteins perform various functions such as catalyzing reactions, forming the backbone and muscles, and even generating movement.

However, is all this variety necessary? Can biology work just as effectively with a reduced number of building blocks and simpler polymers?

Ting Xu, a University of California, Berkeley, polymer scientist, thinks so. She has developed a way to mimic specific functions of natural proteins using only two, four, or six different building blocks ones currently used in plastics and found that these alternative polymers work as well as the real protein and are a lot easier to synthesize than trying to replicate natures design.

As a proof of concept, she used her design method, which is based on machine learning or artificial intelligence, to synthesize polymers that mimic blood plasma. The artificial biological fluid kept natural protein biomarkers intact without refrigeration and even made the natural proteins more resistant to high temperatures an improvement over real blood plasma.

The protein substitutes, or random heteropolymers (RHP), could be a game-changer for biomedical applications since a lot of effort today is put into tweaking natural proteins to do things they were not originally designed to do, or trying to recreate the 3D structure of natural proteins. Drug delivery of small molecules that mimic natural human proteins is one hot research field.

Instead, AI could pick the right number, type, and arrangement of plastic building blocks similar to those used in dental fillings, for example to mimic the desired function of a protein, and simple polymer chemistry could be used to make it.

In the case of blood plasma, for example, the artificial polymers were designed to dissolve and stabilize natural protein biomarkers in the blood. Xu and her team also created a mix of synthetic polymers to replace the guts of a cell, the so-called cytosol. In a test tube filled with artificial biological fluid, the cells nanomachines, the ribosomes, continued to pump out natural proteins as if they didnt care whether the fluid was natural or artificial.

Basically, all the data shows that we can use this design framework, this philosophy, to generate polymers to a point that the biological system would not be able to recognize if it is a polymer or if it is a protein, said Xu, UC Berkeley professor of chemistry and of materials science and engineering. We basically fool the biology. The whole idea is that if you really design it and inject your plastics as a part of an ecosystem, they should behave like a protein. If the other proteins are like, Okay, you are part of us, then thats OK.

The design framework also opens the door to designing hybrid biological systems, where plastic polymers interact smoothly with natural proteins to improve a system, such as photosynthesis. And the polymers could be made to naturally degrade, making the system recyclable and sustainable.

You start to think about a completely new future of plastic, instead of all this commodity stuff, said Xu, who is also a faculty scientist at Lawrence Berkeley National Laboratory.

She and her colleagues published their results in the March 8 issue of the journal Nature.

Xu sees living tissue as a complex mix of proteins that evolved to work together flexibly, with less attention paid to the actual amino acid sequence of each protein than to the functional subunits of the protein, the places where these proteins interact. Just as in a lock-and-key mechanism, where it doesnt make much difference whether the key is aluminum or steel, so the actual composition of the functional subunits is less important than what they do.

And since these natural protein mixtures evolved randomly over millions of years, it should be possible to create similar mixtures randomly, with a different alphabet of building blocks, if you use the right principles to design and select them, relieving scientists of the need to recreate the exact protein mixtures in living tissue.

Nature doesnt do a lot of bottom-up, molecular, precision-driven design like we do in the lab, Xu said. Nature needs flexibility in order to get where it is. Nature doesnt say, lets study the structure of this virus and make an antigen to attack it. Its going to express a library of antigens and from there pick the one that works.

That randomness can be leveraged to design synthetic polymers that mix well with natural proteins, creating biocompatible plastics more easily than todays targeted techniques, Xu says.

Working with applied statistician Haiyan Huang, a UC Berkeley professor, the researchers developed deep learning methods to match natural protein properties with plastic polymer properties in order to design an artificial polymer that functions similarly, but not identically, to the natural protein. For example, in trying to design a fluid that stabilizes specific natural proteins, the most important properties of the fluid are the electric charges of the polymer subunits and whether or not these subunits like to interact with water that is, whether they are hydrophilic or hydrophobic. The synthetic polymers were designed to match those properties, but not other characteristics of the natural proteins in the fluid.

Huang and graduate student Shuni Li trained the deep learning technique a hybrid of classical artificial intelligence (AI) that Huang refers to as a modified variational autoencoder (VAE) on a database of about 60,000 natural proteins. These proteins were broken down into 50 amino acid segments, and the segment properties were compared to those of artificial polymers composed of only four building blocks.

With feedback from experiments by graduate student Zhiyuan Ruan in Xus lab, the team was able to chemically synthesize a random group of polymers, RHPs, that mimicked the natural proteins in terms of charge and hydrophobicity.

We look at the sequence space that nature has already designed, we analyze it, we make the polymer match to what nature already evolved, and they work, Xu said. How well you follow the protein sequence determines the performance of the polymer you get. Extracting information from an established system, such as naturally occurring proteins, is the easiest shortcut to enable us to tease out the right criteria for creating biologically compatible polymers.

Colleagues in the lab of Carlos Bustamante, UC Berkeley professor of molecular and cell biology, of chemistry, and of physics, performed single molecule optical tweezers studies and clearly showed that the RHPs can mimic how proteins behave.

Xu, Huang, and their colleagues are now trying to mimic other protein characteristics to reproduce in plastic the many other functions of natural amino acid polymers.

Right now, our goal is simply stabilizing proteins and mimicking the most basic protein functions, Huang said. But with a more refined design of the RHP system, I think its natural for us to explore enhancing other functions. We are trying to study what sequence compositions can be informative regarding the possible protein functions or behavior that the RHP can carry.

The design platform opens the door to hybrid systems of natural and synthetic polymers but also suggests ways to more easily make biocompatible materials, from artificial tears or cartilage to coatings that can be used to deliver drugs.

If you want to develop biomaterials to interact with your body, to do tissue engineering or drug delivery, or you want to do a stent coating, you have to be compatible with biological systems, Xu said. What this paper is telling you is: Here are the design rules. This is how you should interface with biological fluids.

Her ultimate goal is to totally rethink how biomaterials are currently designed because current methods focused primarily on mimicking the amino acid structures of natural proteins are not working.

The Food and Drug Administration hasnt approved any new material for polymer biomaterials for decades, and I think the reason is that a lot of synthetic polymers are not really working we are pursuing the wrong direction, she said. We are not letting the biology tell us how the material should be designed. We are looking at individual pathways, individual factors, and not looking at it holistically. The biology is really complicated, but its very random. You really have to speak the same language when dealing with materials. Thats what I want to share with the materials community.

Reference: Population-based heteropolymer design to mimic protein mixtures by Zhiyuan Ruan, Shuni Li, Alexandra Grigoropoulos, Hossein Amiri, Shayna L. Hilburg, Haotian Chen, Ivan Jayapurna, Tao Jiang, Zhaoyi Gu, Alfredo Alexander-Katz, Carlos Bustamante, Haiyan Huang and Ting Xu, 8 March 2023, Nature.DOI: 10.1038/s41586-022-05675-0

The study was funded by the U.S. Department of Defense, the National Science Foundation, the Department of Energys Office of Science, and the Alfred P. Sloan Foundations Matter-to-Life initiative.

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Fooling Biology: Can Synthetic Polymers Replace the Body's ... - SciTechDaily

Cell Biology

Understanding how to better prescribe probiotics based on our individual microbiome profiles – News-Medical.Net

Bacteria have thousands of genes and functions that we, the human host, do not have. For instance, bacteria can help us digest fiber, provide support to our immune systems, and absorb important nutrients. But reaping the benefits of "good bacteria" is easier said than done.

At the moment, there are as many types of probiotics on the shelves as there are people on the planet. Having so many options at our disposal makes it difficult for the average consumer to know which ones are "the best" for our own bodies or ailments.

Microbiologists like Andrea Azcarate-Peril, PhD, who specializes in the study of the microbiome the collection of genomes from all microbes naturally living inside of us are trying to understand how to better prescribe probiotics based on our individual microbiome profiles.

Probiotics have been around for a very, very long time. We've studied them for decades. The problem is that some people will take probiotics, and they will do these miraculous things for them. But that doesn't work for everyone."

Azcarate-Peril, associate professor of medicine and nutrition in the School of Medicine at UNC

More FDA regulations on probiotics are necessary to ensure that consumers get what they pay for live active bacteria in their probiotics. Azcarate-Peril says that if you want to start boosting your microbiome more effectively and reliably, rotate your probiotics and consume a variety of fermented foods such as kimchi, kombucha, kefir, yogurt, and cheeses.

"Rotate the probiotics," said Azcarate-Peril, who is also a member of the Center for Gastrointestinal Biology and Disease. "You don't need to marry to one probiotic. And most importantly, eat a lot of fermented foods. If you can tolerate lactose, that's what you want. You want to have real food that has plenty of non-pathogenic bacteria."

What she says next may cause you to re-think your next trip to your nearest fast-food chain.

Let's say you're making your own burger at home. You form the beef patty, wash, and cut up a few pieces of tomato and lettuce. Even after giving it a good rinse, fresh vegetables still have a healthy number of bacteria on it enough to re-seed your microbiome.

If you go and get the same thing from a fast-food chain, you are likely missing out on those healthy bacteria because of the food preparation process.

"From the origin of the raw materials, how the food is produced, and with added preservatives to make them last longer" said Azcarate-Peril. "This is understandably because they don't want to make someone sick with a food-borne disease." But this process also limits the intake of foods that feed a microbiome to keep it balanced.

Azcarate-Peril is also director of the UNC Microbiome Core, which provides UNC-Chapel Hill's research community with the facilities and expertise to characterize complex microbial communities and microbial interactions. The core has a number of projects going on at the moment.

Our brains experience three stages of cognitive aging: successful aging, which involves no loss of mental function; normal cognitive decline, which includes occasional forgetfulness or loss of things; and dementia or Alzheimer's disease.

There is a multi-year window in which one may be able to delay cognitive decline before normal cognitive aging and dementia set in. Azcarate-Peril and John Gunstad, PhD, of Kent State University, conducted a randomized clinical trial in middle-aged and older adults to see if there was a correlation between probiotics and mild cognitive impairment.

In their study, they found that patients who were given Lactobacillus rhamnosus had a decrease in the relative abundance of the Prevotella and Dehalobacterium bacterium, which coincided with an improved cognitive score. In light of this new correlation, the researchers are trying to determine if Prevotella and Dehalobacterium are inherently "good" or "bad" for cognition. As for right now, they cannot say if the bacterium causes anything.

"If we are able to modulate the gut microbiota, during that window of opportunity, maybe we can delay conditions such as dementia or Alzheimer's," said Azcarate-Peril. "But we will have to see."

The only organ that can not be transplanted from one body to another is the intestine.

Since fecal samples are simple to collect and tests are non-invasive, many studies use them to study the gut microbiome. Fecal bacteria, on the other hand, are frequently transitory and just move through the intestines without taking hold. This may not be entirely representative of the bacteria that lives in the small intestine, which represents twenty-two feet of intestinal wall that bacteria can attach to.

Azcarate-Peril is in collaboration with Scott Magness, PhD, an associate professor in the UNC/NCSU Joint Department of Biomedical Engineering and in the UNC Department of Cell Biology and Physiology, to better study intestinal tissues and the microbiome with a little bit of bioengineering. Using a small piece of donated intestinal tissue, Magness is able to collect stem cells and grow organoids, while Azcarate-Peril is able to collect the microbes from the intestine.

"Now we can study what's in there and what is happening in the small intestine," said Azcarate-Peril. "It's super interesting, because now we have enough donors, and we can start making some generalizations. And this is super exciting, because there are only a few studies on the microbiome of the small intestine."

Overall, Azcarate-Peril says that if your tummy is happy, you're happy. If your tummy is not happy, you're not happy.

Source:

Journal reference:

Aljumaah, M. R., et al. (2022). The gut microbiome, mild cognitive impairment, and probiotics: A randomized clinical trial in middle-aged and older adults.Clinical Nutrition (Edinburgh, Scotland). doi.org/10.1016/j.clnu.2022.09.012.

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Understanding how to better prescribe probiotics based on our individual microbiome profiles - News-Medical.Net

Cell Biology

NYC Mayor Eric Adams Joined Top Biomedical Researchers to Usher in the Center for Engineering and Precision – EIN News

New York City Mayor Eric Adams speaks at the grand opening for the Center for Engineering and Precision Medicine on March 29, 2023.

Rensselaer Polytechnic Institute President Martin A. Schmidt 81, Ph.D., and Center for Engineering and Precision Medicine Co-Director Jonathan Dordick, Ph.D., tour the new center during the March 29, 2023 grand opening in New York City.

Dennis S. Charney, M.D., the Anne and Joel Ehrenkranz Dean of Icahn Mount Sinai, speaks at the grand opening for the Center for Engineering and Precision Medicine on March 29, 2023 in New York City.

Center for Engineering and Precision Medicine Co-Directors Jonathan Dordick, Ph.D., and Priti Balchandani, Ph.D., at the grand opening on March 29, 2023.

Keynote speakers Derrick Rossi, Ph.D., Interim CEO of New York Stem Cell Foundation, and Roderic I. Pettigrew, Ph.D., M.D., CEO of Engineering Health, tour the Center for Engineering and Precision Medicine at its grand opening on March 29, 2023 in New York City.

Rensselaer Polytechnic Institute and the Icahn School of Medicine at Mount Sinai partner to advance medical research at life sciences hub

New York City Mayor Eric Adams

Rensselaer Polytechnic Institute and the Icahn School of Medicine at Mount Sinai partner to advance medical research at life sciences hub

The grand opening of the Center for Engineering and Precision Medicine (CEPM), a partnership between Rensselaer Polytechnic Institute (RPI) and the Icahn School of Medicine at Mount Sinai (Icahn Mount Sinai), was held yesterday at the Hudson Research Center (HRC) at 619 West 54th Street.

The center is the latest in a 10+ year partnership between RPI, a world-renowned technological research university known for its engineering, technology, and science programs, and Icahn Mount Sinai, the academic arm of the Mount Sinai Health System, which includes eight hospitals and a vast network of ambulatory practices throughout the greater New York City region. The HRC is a 320,000-square-foot, mixed-use hub for innovation in New York Citys growing life sciences sector.

We are thrilled to open the doors to the Center for Engineering and Precision Medicine, said Rensselaer President Martin A. Schmidt, Ph.D. CEPM will transform the diagnosis and treatment of cancer, Alzheimers, infectious diseases, and more by advancing state-of-the-art technologies and focusing on a personalized approach. CEPM, the third of RPIs New York City-based research centers, will also provide exceptional educational opportunities for the next generation of researchers, medical professionals, and life sciences entrepreneurs.

Leveraging the strength of RPI and Icahn Mount Sinai, CEPM bridges research, technology development and commercialization, and education. CEPM is one of the first life science centers of its kind in New York City and the nation to integrate engineering and biomedical sciences with education, training, and research collaborations to radically improve human health.

CEPM is built on the tenet that engineering is fundamental to understanding biomedical phenomena and developing the next generation of precision diagnostics and therapeutics for human health and well-being. RPI and Icahn Mount Sinai are well-positioned to seamlessly integrate research and education in engineering with medicine and transform personalized medicine. Critically, a major distinguishing feature of CEPM is the immense diversity in patients within the Mount Sinai Health System. This diversity, together with the analytical capabilities of engineering, is critical in advancing precision medicine.

The Center for Engineering and Precision Medicine combines the biomedical excellence of Icahn Mount Sinai with the engineering expertise of RPI to create an academic research hub that will make fundamental discoveries and develop new treatments that will improve the lives of patients suffering from the most complex diseases, said Dennis S. Charney, M.D., the Anne and Joel Ehrenkranz Dean of Icahn Mount Sinai.

Housed in 23,000 square feet of lab space on the 9th floor of the HRC, CEPM will benefit from the areas abundance of research talent and is in the process of recruiting faculty and staff. The space provides both wet lab and dry lab capabilities with high-performance computational infrastructure to seamlessly perform complex experiments and build advanced technologies to diagnose, treat, and manage diseases at a patients level. Office space and open cubicles surround the lab space to create a cohesive and collaborative research environment to promote interdisciplinary teamwork.

The Center for Engineering and Precision Medicine is more than a hub for research and education its a bridge to the future, said New York City Mayor Eric Adams. Our administration is harnessing the momentum of the life sciences industry to create access to next-generation jobs for everyone. Last year, Governor Hochul and I announced SPARC Kips Bay, an education and innovation hub that will be the first of its kind in New York City, which will generate $25 billion in economic impact to the city and create 10,000 jobs. Together, we are going to make sure New York City leads the globe in life sciences.

The New York Stem Cell Foundation (NYSCF) Research Institute, a nonprofit organization with a mission to accelerate cures for the major diseases of our time, is on the second and third floors of the HRC. Stem cell research plays a critical role in engineering tissue repair and in developing various cell types for drug discovery screening.

These two institutions are widely recognized leaders in engineering and medicine, and we are delighted to welcome the Center for Engineering and Precision Medicine to the Hudson Research Center by hosting the grand opening event, said Derrick Rossi, Ph.D., Interim CEO of NYSCF. The synergies between NYSCFs stem cell biology and the engineering and medical expertise at CEPM will lead to new and important collaborations to accelerate discoveries that directly reach patients.

Speakers included Schmidt and Charney, Mayor Adams, Senator Charles Schumer and Senator Kirsten Gillibrand (via video), and New York City Economic Development Corporation (NYCEDC) President and CEO Andrew Kimball.

As we continue to establish New York City as the leader in the life sciences industry, we must continue to bolster innovation that will create new jobs and spur meaningful research, said Kimball. The Center for Engineering and Precision Medicine will uniquely bridge biology, health care, and technology to advance cutting-edge discoveries and accelerate breakthrough treatment for intractable diseases, advancing individualized treatment, and improving quality of life for all New Yorkers. We are excited to continue working with our partners to spark new opportunities in this rapidly growing industry. The keynote speakers were Rossi and Roderic I. Pettigrew, Ph.D., M.D., CEO of Engineering Health and Executive Dean for Engineering Medicine at Texas A&M University, in partnership with Houston Methodist Hospital.

Additional speakers included CEPM Co-Directors Jonathan Dordick, Ph.D., Institute Professor of Chemical and Biological Engineering, Biomedical Engineering, and Biological Sciences at Rensselaer; and Priti Balchandani, Ph.D., Professor of Diagnostic, Molecular and Interventional Radiology, Neuroscience, and Psychiatry at Icahn Mount Sinai; as well as Deepak Vashishth, Ph.D., Director of the Center for Biotechnology and Interdisciplinary Studies at Rensselaer and CEPM Associate Director.

The Center for Engineering and Precision Medicine will enable breakthroughs in neuromodulation, immune resilience, and regenerative and reparative medicine, said CEPM Co-Director Dordick. We will give top talent with ambitious ideas the resources they need to more effectively advance personalized medicine to address intractable diseases and benefit patients.

CEPM represents the evolution of a successful partnership between Mount Sinai and Rensselaer that has secured over $80 million in shared research funding since 2013. CEPM will drive advances in point-of-care and point-of-use devices and diagnostics; microphysiological platforms for discovery and diagnosis; robotic surgery; biomedical imaging; therapeutics biomanufacturing; and artificial intelligence and machine learning applied to biomedical data. The Center for Engineering and Precision Medicine is creating a direct opportunity for exceptional engineers to apply their knowledge and skill toward the transformation of medicine and improvement of human health, said CEPM Co-Director Balchandani.

CEPM will offer a joint Ph.D. to train students in engineering medicine with expertise in reparative medicine, and neuro- and immuno- engineering through educational courses and research training. It will involve immersions in engineering, entrepreneurship and commercialization, and clinical rotation and shadowing to create a translational mindset at the onset of the program and produce a new breed of Ph.D.s capable of inventing new technologies to address unmet clinical needs. The development of certificate programs will broaden CEPMs academic mission and facilitate entrepreneurship and commercialization of advanced technologies and medical devices.

The Center for Engineering and Precision Medicine presents exciting opportunities for researchers, students, and, ultimately, patients, said Vashishth. The treatments and technologies developed at CEPM will decrease side effects and increase effectiveness for patients and usher an inclusive and healthier future for medicine and health care.

We are proud to welcome Rensselaer and Mount Sinai as they launch the new Center for Engineering and Precision Medicine in the Hudson Research Center, said Matthew Weir, President of Elevate Research Properties. This new center will serve as an important anchor for the growing New York City research ecosystem.

About Rensselaer Polytechnic Institute: Founded in 1824, Rensselaer Polytechnic Institute is Americas first technological research university. Rensselaer encompasses five schools, over 30 research centers, more than 140 academic programs, including 25 new programs, and a dynamic community comprised of over 6,800 students and 104,000 living alumni and alumnae. Rensselaer faculty and graduates include upward of 155 National Academy members, six members of the National Inventors Hall of Fame, six National Medal of Technology winners, five National Medal of Science winners, and a Nobel Prize winner in Physics. With nearly 200 years of experience advancing scientific and technological knowledge, Rensselaer remains focused on addressing global challenges with a spirit of ingenuity and collaboration. To learn more, please visit http://www.rpi.edu.

About the Icahn School of Medicine at Mount Sinai: The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population. Ranked 14th nationwide in National Institutes of Health (NIH) funding and among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 3,000 full-time scientists, educators and clinicians work within and across 34 academic departments and 35 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, as well as gastrointestinal and liver diseases. Icahn Mount Sinai offers highly competitive MD, PhD, and Masters degree programs, with current enrollment of approximately 1,300 students. It has the largest graduate medical education program in the country, with more than 2,000 clinical residents and fellows training throughout the Health System. In addition, more than 550 postdoctoral research fellows are in training within the Health System. To learn more, please visit https://icahn.mssm.edu/.

About Taconic Partners: Since 1997, Taconic Partners has acquired, redeveloped and repositioned over 12 million square feet of commercial office and mixed-use space, as well as over 6,500 units of luxury and workforce housing. As a fully integrated real estate company with a keen eye for uncovering value, its diverse capabilities are evidenced by its multifaceted success with luxury properties, as well as adaptive reuse and urban revitalization projects. In New York City, Taconic is advancing over 650,000 square feet of life sciences space at 125 West End Avenue as well as at the Hudson Research Center at 619 West 54th Street. Other active Taconic projects include 817 Broadway, 311 West 42nd Street and Essex Crossing on the Lower East Side. The firm also manages various real estate funds on behalf of institutional and pension fund investors. For more information visit: http://www.taconicpartners.com

About Silverstein Properties: Silverstein Properties is a privately held, full-service real estate development, investment and management firm based in New York. Founded in 1957 by Chairman Larry Silverstein, the company has developed, owned and managed more than 40 million square feet of commercial, residential, retail and hotel space. Recent projects include 7 World Trade Center, the first LEED-certified office tower in New York City (2006), 4 World Trade Center (2013), the Four Seasons Downtown (2016), One West End (2017) and 3 World Trade Center (2018). The company has been recognized as one of the Best Places to Work in New York City by Crains New York Business for eight years in a row. For further information on Silverstein Properties, please visit http://www.silversteinproperties.com.

About New York Stem Cell Foundation Research Institute: The New York Stem Cell Foundation (NYSCF) Research Institute is an independent non-profit organization accelerating cures and better treatments for patients through stem cell research. The NYSCF global community includes over 200 researchers at leading institutions worldwide, including the NYSCF Druckenmiller Fellows, the NYSCF Robertson Investigators, the NYSCF Robertson Stem Cell Prize Recipients, and NYSCF Research Institute scientists and engineers. The NYSCF Research Institute is an acknowledged world leader in stem cell research and in the development of pioneering stem cell technologies, including the NYSCF Global Stem Cell Array, which is used to create cell lines for laboratories around the globe. NYSCF focuses on translational research in an accelerator model designed to overcome barriers that slow discovery and replace silos with collaboration.

Contact: Rensselaer Polytechnic Institute Katie Malatino malatk@rpi.edu 838-240-5691

Mount Sinai Karin Eskenazi karin.eskenazi@mssm.edu 332-257-1538

Taconic Partners/Silverstein Properties Johann Hamilton johann@relevanceinternational.com 917-887-1750

New York Stem Cell Foundation David McKeon dmckeon@nyscf.org 212-365-7440

Katie MalatinoRensselaer Polytechnic Institute+1 838-240-5691malatk@rpi.edu

Rensselaer Polytechnic Institute President Martin A. Schmidt 81, Ph.D., and Center for Engineering and Precision Medicine Co-Director Jonathan Dordick, Ph.D., tour the new center during the March 29, 2023 grand opening in New York City.

Dennis S. Charney, M.D., the Anne and Joel Ehrenkranz Dean of Icahn Mount Sinai, speaks at the grand opening for the Center for Engineering and Precision Medicine on March 29, 2023 in New York City.

Center for Engineering and Precision Medicine Co-Directors Jonathan Dordick, Ph.D., and Priti Balchandani, Ph.D., at the grand opening on March 29, 2023.

Keynote speakers Derrick Rossi, Ph.D., Interim CEO of New York Stem Cell Foundation, and Roderic I. Pettigrew, Ph.D., M.D., CEO of Engineering Health, tour the Center for Engineering and Precision Medicine at its grand opening on March 29, 2023 in New York City.

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NYC Mayor Eric Adams Joined Top Biomedical Researchers to Usher in the Center for Engineering and Precision - EIN News

Cell Biology

Funding boost for world-first cell transplantation research for … – The National Tribune

Griffith Universitys world-first study into cell transplantation to repair injuries to the nervous system has received a major boost thanks to a $5.4 million funding extension from the Motor Accident Insurance Commission (MAIC).

Griffiths Clem Jones Centre for Neurobiology and Stem Cell Research, headed by Professor James St John, is developing cell transplantation therapies to treat injuries of the nervous system.

Professor St John said spinal cord injury, peripheral nerve injuries and brain injuries are of particular concern for people who suffer road trauma and can leave victims with life-long paralysis and reduced quality of life.

The research team has created a world-first cellular nerve bridge technology which has already received two major national awards, the NHMRC Marshall and Warren Innovation Award 2019 and the Research Australia Discovery Award 2020-2021, he said.

The innovative technology enables the rapid generation of cellular nerve bridges which can be easily handled by surgeons for transplantation to treat spinal cord injury.

This latest round of funding will allow the research team to expand the nerve bridge technology to a wider range of nervous system injuries including peripheral nerve and brain injuries.

We are now on the verge of a human Phase 1 clinical trial for treating chronic spinal cord injury, and through the ongoing support of MAIC we are delighted we have been able to deliver it right here in Queensland.

The Clem Jones Centre team has successfully demonstrated the efficacy of the nerve bridges for treating spinal cord injury in preclinical models.

Professor James St John said the funding has enabled the team of more than 30 researchers to rapidly create, test and improve incredible technologies that were just a dream a few years ago.

By combining discovery research with translational research, we can fast-track the delivery of therapies to the clinic, Professor St John said.

Our research team is successful because of the diversity of our ideas.

Our team members come from 12 different countries, and we cover all areas of research from discovery cell biology, to bioengineering, surgery, rehabilitation and clinical trial planning.

It also means we can simultaneously develop and translate the research into clinical outcomes.

The new MAIC funding of $5.4 million brings the total MAIC investment into the therapy development to more than $16 million since 2017, with the major focus of the research being to develop a therapy for spinal cord injury.

Insurance Commissioner Neil Singleton said MAIC was delighted to continue to support Professor St John and his team in their potentially ground-breaking work.

Road trauma remains one of the leading causes of both spinal cord and brain injuries which can have devastating impacts on the lives of everyday Queenslanders and their families, Mr Singleton said.

Our continued support of this important research reflects our commitment to investing in initiatives which can make a real difference in mitigating the impacts of road trauma.

We are excited about the opportunities that may emerge as this research proceeds to a clinical trial in the near future.

The Clem Jones Centre for Neurobiology and Stem Cell Research was established in 2016 with funding from the Clem Jones Foundation ($2.4 million since 2016) with the aim of creating therapies to treat injuries and diseases of the nervous system.

The Centre is part of the Griffith Institute for Drug Discovery and the Menzies Health Institute Queensland, with the spinal cord project a legacy life-long project of the late Professor Emeritus Alan Mackay-Sim.

The Centre has also been strongly supported by the Perry Cross Spinal Research Foundation with more than $2 million in funding.

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Cell Biology

Precigen Announces Further Advancement of UltraCAR-T Platform … – BioSpace

Milestone represents the first patient dosed with the next generation UltraCAR-T, incorporating PD-1 checkpoint inhibition in addition to three effector genes Proprietary technology for checkpoint blockade intrinsic to UltraCAR-T cells avoids the need for combination with a systemic checkpoint inhibitor, potentially limiting cost and systemic toxicity

GERMANTOWN, Md., March 29, 2023 /PRNewswire/ --Precigen, Inc.(Nasdaq: PGEN), a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, today announced that the first patient has been dosed in the Phase 1/1b dose escalation/dose expansion study (clinical trial identifier: NCT05694364) of PRGN-3007 in advanced ROR1-positive (ROR1+) hematological and solid tumors. The target patient population for the study includeschronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and diffuse large B-cell lymphoma (DLBCL) and solid tumors, including breast adenocarcinomas encompassing triple negative breast cancer (TNBC). There are estimated to be more than 100,000 patients diagnosed in both the hematological and TNBC target populations in the United States, European Union and Japan in 2023.a

PRGN-3007 UltraCAR-T is a first-in-class investigational multigenic, autologous CAR-T cell therapy utilizing Precigen's clinically validated advanced non-viral gene delivery system and well-established overnight, decentralized manufacturing process. Precigen has further advanced the UltraCAR-T platform to address the inhibitory tumor microenvironment by incorporating intrinsic checkpoint blockade without the need for complex and costly gene editing techniques. PRGN-3007 is engineered using a single multicistronic transposon plasmid to simultaneously express a chimeric antigen receptor (CAR) targeting ROR1, membrane-bound interleukin15 (mbIL15), a kill switch, and a novel mechanism for the intrinsic blockade of PD-1 gene expression. The innovative design of PRGN-3007, where the blockade of PD-1 expression is intrinsic and localized to UltraCAR-T cells, is aimed at avoiding systemic toxicity and the high cost of checkpoint inhibitors by eliminating the need for combination treatment.

The Phase 1/1b clinical trial is an open-label study designed to evaluate the safety and efficacy of PRGN-3007 in patients with advanced ROR1+ hematological (Arm 1) and solid (Arm 2) tumors. The study is enrolling in two parts: an initial 3+3 dose escalation in each arm followed by a dose expansion at the maximum tolerated dose (MTD). Arm 1 and Arm 2 are enrolling in parallel. The investigator-initiated study is being conducted in collaboration with the H. Lee Moffitt Cancer Center & Research Institute (Moffitt).

"We are excited to work with Precigen and announce that the first patient, a CLL patient, has been dosed in the first-in-human study of PRGN-3007 UltraCAR-T," said Javier Pinilla-Ibarz, MD, PhD, Senior Member, Lymphoma Section Head and Director of Immunotherapy, Malignant Hematology Department, Moffitt, and Principal Investigator for the PRGN-3007 clinical study. "ROR1 is a promising target for addressing a wide variety of tumors and we are hopeful that the PRGN-3007 study will further the development of this novel CAR-T treatment, which combines intrinsic PD-1 inhibition and ease of administration from the validated overnight manufacturing of UltraCAR-T performed at our medical center bringing therapy to patients within one day."

"Dosing the first patient with PRGN-3007, the next generation of UltraCAR-T incorporating PD-1 inhibition, is a significant milestone for the UltraCAR-T platform," saidHelen Sabzevari, PhD, President and CEO ofPrecigen. "The PRGN-3007 study targets a broad range of hematological and solid tumor indications and this milestone helps us move closer to our vision for UltraCAR-T, which aims to deliver a library of personalized autologous UltraCAR-T therapies usingovernight manufacturingat the patient's medical center."

Precigen: Advancing Medicine with PrecisionPrecigen (Nasdaq: PGEN) is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of gene and cell therapies using precision technology to target the most urgent and intractable diseases in our core therapeutic areas of immuno-oncology, autoimmune disorders, and infectious diseases. Our technologies enable us to find innovative solutions for affordable biotherapeutics in a controlled manner. Precigen operates as an innovation engine progressing a preclinical and clinical pipeline of well-differentiated therapies toward clinical proof-of-concept and commercialization. For more information about Precigen, visit http://www.precigen.comor follow us on Twitter @Precigen, LinkedInor YouTube.

About Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1)ROR1 is a type I orphan-receptor that is expressed during embryogenesis and by certain hematological and solid tumors but is undetectable on normal adult tissues.1-3 ROR1 plays an important role in oncogenesis by activating cell survival signaling events, particularly the non-canonical WNT signaling pathway.4 Aberrant expression of ROR1 is detected in multiple hematological malignancies including CLL5, MCL6, ALL7, and DLBCL.8 Elevated ROR1 expression is detected in various solid tumors, including breast adenocarcinoma encompassing TNBC, pancreatic cancer, ovarian cancer, Ewing's sarcoma and lung adenocarcinoma.9-14 Many human breast adenocarcinomas express high levels of ROR1, which is not expressed by normal breast tissue.15

UltraCAR-TUltraCAR-T is a multigenic autologous CAR-T platform that utilizes Precigen's advanced non-viral Sleeping Beauty system to simultaneously express an antigen-specific CAR to specifically target tumor cells, mbIL15 for enhanced in vivo expansion and persistence, and a kill switch to conditionally eliminate CAR-T cells for a potentially improved safety profile. Precigen has advanced the UltraCAR-T platform to address the inhibitory tumor microenvironment by incorporating a novel mechanism for intrinsic checkpoint blockade without the need for complex and expensive gene editing techniques. UltraCAR-T investigational therapies are manufactured via Precigen's overnight manufacturing process using the proprietary UltraPorator electroporation system at the medical center and administered to patients only one day following gene transfer. The overnight UltraCAR-T manufacturing process does not use viral vectors and does not require ex vivo activation and expansion of T cells, potentially addressing major limitations of current T cell therapies.

UltraPoratorThe UltraPorator system is an exclusive device and proprietary software solution for the scale-up of rapid and cost-effective manufacturing of UltraCAR-T therapies and potentially represents a major advancement over current electroporation devices by significantly reducing the processing time and contamination risk. The UltraPorator device is a high-throughput, semi-closed electroporation system for modifying T cells using Precigen's proprietary non-viral gene transfer technology. UltraPorator is being utilized for clinical manufacturing of Precigen's investigational UltraCAR-T therapies in compliance with current good manufacturing practices.

TrademarksPrecigen, UltraCAR-T, UltraPorator, and Advancing Medicine with Precision are trademarks ofPrecigenand/or its affiliates. Other names may be trademarks of their respective owners.

Cautionary Statement Regarding Forward-Looking StatementsSome of the statements made in this press release are forward-looking statements. These forward-looking statements are based upon the Company's current expectations and projections about future events and generally relate to plans, objectives, and expectations for the development of the Company's business, including the timing and progress of preclinical studies, clinical trials, discovery programs and related milestones, the promise of the Company's portfolio of therapies, and in particular its CAR-T and AdenoVerse therapies. Although management believes that the plans and objectives reflected in or suggested by these forward-looking statements are reasonable, all forward-looking statements involve risks and uncertainties, including the possibility that the timeline for the Company's clinical trials might be impacted by the COVID-19 pandemic, and actual future results may be materially different from the plans, objectives and expectations expressed in this press release. The Company has no obligation to provide any updates to these forward-looking statements even if its expectations change. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. For further information on potential risks and uncertainties, and other important factors, any of which could cause the Company's actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in the Company's most recent Annual Report on Form 10-K and subsequent reports filed with the Securities and Exchange Commission.

Referencesa GlobalData Epidemiology Market Size Research.1Balakrishnan, A., et al., Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues. Clin Cancer Res, 2017. 23(12): p. 3061-3071.2Green, J.L., et al., ROR receptor tyrosine kinases: orphans no more. Trends in Cell Biology, 2008. 18(11): p. 536-544.3Rebagay, G., et al., ROR1 and ROR2 in Human Malignancies: Potentials for Targeted Therapy. Front Oncol, 2012. 2(34).4Zhao Y, et al., Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies. Front. Oncol, 2021.5Baskar, S., et al., Unique Cell Surface Expression of Receptor Tyrosine Kinase ROR1 in Human B-Cell Chronic Lymphocytic Leukemia. Clin Cancer Res, 2008. 14(2): p. 396-404.6Hudecek, M., et al., The B-cell tumorassociated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood, 2010. 116(22): p. 4532-4541.7Enayati H, et al., Expression of ROR1 Gene in Patients with Acute Lymphoblastic Leukemia. IJBC 2019; 11(2): 57-62.8Ghaderi, A., et al., ROR1 Is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells. Biomedicines, 2020. 8(6).9Zhang, S., et al., The onco-embryonic antigen ROR1 is expressed by a variety of human cancers. Am J Pathol, 2012. 181(6): p. 1903-10.10Zhang, S., et al., ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS One, 2012.7(3): p. e31127.11Potratz, J., et al., Receptor tyrosine kinase gene expression profiles of Ewing sarcomas reveal ROR1 as a potential therapeutic target in metastatic disease. Mol Oncol, 2016. 10(5): p. 677-92.12Zheng, Y.Z., et al., ROR1 is a novel prognostic biomarker in patients with lung adenocarcinoma. Sci Rep, 2016. 6: p. 36447.13Choi, M.Y., et al., Pre-clinical Specificity and Safety of UC-961, a First-In-Class Monoclonal Antibody Targeting ROR1. Clin Lymphoma Myeloma Leuk, 2015. 15 Suppl: p. S167-9.14Balakrishnan, A., et al., Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues. Clin Cancer Res, 2017. 23(12): p. 3061-3071.15Zhang S. et al., ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS One, 2012, 7:e31127.

Investor Contact:Steven M. HarasymVice President, Investor RelationsTel: +1 (301) 556-9850investors@precigen.com

Media Contacts:Donelle M. Gregorypress@precigen.com

Glenn SilverLazar-FINN Partnersglenn.silver@finnpartners.com

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Cell Biology

Heart attack study could change the game in regenerative medicine – EurekAlert

image:Alexandre Colas, Ph.D. view more

Credit: Sanford Burnham Prebys

LA JOLLA, CALIF. Mar 29, 2023 -Sanford Burnham Prebys researchers have identified a group of proteins that could be the secret to cellular reprogramming, an emerging approach in regenerative medicine in which scientists transform cells to repair damaged or injured body tissues. The researchers were able to reprogram damaged heart cells to repair heart injuries in mice following a heart attack. The findings, which appear in the journalNature Communications, could one day transform the way we treat a variety of diseases, including cardiovascular disease, Parkinsons and neuromuscular diseases.

Even if a person survives a heart attack, there could still be long-term damage to the heart that increases the risk of heart problems down the line, says lead authorAlexandre Colas, Ph.D., an assistant professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys. Helping the heart heal after injury is an important medical need in its own right, but these findings also pave the way for wider applications of cell reprogramming in medicine.

Even though each of our cells has the same number of genesapproximately 20,000cells can select which genes to turn on and turn off to change what they look like and what they do. This is the foundation of cellular reprogramming.

Cellular reprogramming could, in theory, allow us to control the activity and appearance of any cell, says Colas. This concept has huge implications in terms of helping the body regenerate itself, but barriers to reprogramming mechanisms have prevented the science from moving from the lab to the clinic.

The researchers identified a group of four proteins, named AJSZ, that help solve this problem.By blocking the activity of these proteins, we were able to reduce scarring on the heart and induce a 50% improvement in overall heart function in mice that have undergone a heart attack, says Colas.

Although the researchers were primarily focused on heart cells, they determined that AJSZ is universal to all cell types. This suggests that targeting AJSZ could be a promising treatment approach for a variety of human diseases.

This is helping us solve a very big problem that a lot of researchers are interested in, says Colas. Even more important, this breakthrough is a significant step forward on our way to turning these promising biological concepts into real treatments.

The next steps in translating their discovery into a potential treatment is to explore different ways of blocking the function of the AJSZ proteins. According to Colas, the most promising option would be to use a small molecule drug to block the activity of AJSZ.

We need to find a way to inhibit these proteins in a way we can control to make sure we are only reprogramming the cells that need it, says Colas. We will be screening for drugs that can help us inhibit these proteins in a controlled and selective manner in the coming months.

###

Additional authors of the study include Maria A. Missinato, Michaela Lynott, Michael S. Yu, Anas Kervadec, Yu-Ling Chan, Christopher Lee, Prashila Amatya, Hiroshi Tanaka, Chun-Teng Huang, Pier Lorenzo Puri, Peter D. Adams and Alessandra Sacco, Sanford Burnham Prebys; Sean Murphy, Suraj Kannan, Chulan Kwon and Peter Andersen, Johns Hopkins University School of Medicine; and Li Qian, University of North Carolina at Chapel Hill.

The study was supported by grants from the California Institute of Regenerative Medicine (DISC2-10110), the National Institutes of Health (R01 HL153645, R01 HL148827, R01 HL149992, R01 AG071464), and Sanford Burnham Prebys institutional support to Alexandre Colas.

The studys DOI is 10.1038/s41467-023-37256-8.

About Sanford Burnham Prebys

Sanford Burnham Prebys is an independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 45 years, our research has produced breakthroughs in cancer, neuroscience, immunology and childrens diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us atSBPdiscovery.orgor on Facebookfacebook.com/SBPdiscoveryand on Twitter@SBPdiscovery.

Nature Communications

Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells

27-Mar-2023

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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Cell Biology

20-Year Study May Upend Long-Held Theory About Chromosomes and Cancer – Newswise

FOR IMMEDIATE RELEASE

Newswise Johns Hopkins Medicine scientists say their 20-year study of more than 200 people with premature aging syndromes caused by abnormally short telomeres, or shortened repetitive DNA sequences at the ends of chromosomes, may upend long-held scientific dogma and settle conflicting studies about how and whether short telomeres contribute to cancer risk.

The research, which has the potential to guide treatments and cancer screening among people with short telomere syndromes, appears in the April 10 issue of Cancer Cell.

For decades, some studies in animal models and cells have linked the existence of extremely short telomeres with instability of chromosomes, the X-shaped structures that house genes. Such instability is a common feature of cancer cells.

The new study suggests that chromosomal instability may not be the reason that people with short telomere syndromes are prone to a small but increased risk of certain types of solid cancers. Rather, the researchers say cancer predisposition in these patients may be linked to immune system cells that age and die or vanish prematurely.

This study reinforces how incredibly important the immune system is in surveilling our cells for cancer as we age, says Mary Armanios, M.D., professor of oncology and director of the telomere center at the Johns Hopkins Kimmel Cancer Center, and professor of genetic medicine, molecular biology and genetics, and pathology at the Johns Hopkins University School of Medicine.

Telomeres naturally shorten with age. People whose telomeres are highly truncated at or below the 10th percentile of human telomere lengths have some traits of premature aging. Their hair turns gray at a young age, for example, and they develop pulmonary fibrosis, or scarring of the lungs, earlier than most people do.

While short telomere syndromes are relatively rare, its estimated that some 50% of people with the most common type of pulmonary fibrosis have short telomeres.

For the new study, Armanios and pediatric oncologist Kristen Schratz, M.D., kept track of some 226 people with short telomere syndromes seen and diagnosed at The Johns Hopkins Hospital and other hospitals across the U.S. between 2003 and 2022. More than half of the participants were male, and their median age was 50 by the end of the study.

Over the two decades, 35 people (15%) in the group developed cancer, nearly all identified in adulthood. Twenty-one had blood cancers, either myelodysplastic syndrome or acute myeloid leukemia, both of which have long been associated with short telomere syndromes.

Of the 35, 14 developed 16 solid tumors, and 14 of them were squamous cancers, including those of the mouth, anus and skin that may also develop in people whose immune systems are suppressed. Half of these cancers were diagnosed early and were removed by surgery.

The number of cancers was lower than what would be expected if short telomeres fueled genome instability, and these are not the types of cancers youd expect in people with syndromes that mimic premature aging, says Armanios.

In addition, most of the patients who developed solid tumors (13 of 14) were males, and the molecular reasons why males with short telomeres tend to develop these tumors is worth further study, says Armanios.

During the 20-year span, population statistics suggest the 226 people in the study should have experienced about 19 cases of the most common lethal cancers mostly associated with aging, including lung, colon, pancreatic, kidney, bladder and uterine cancers.

The researchers sequenced the whole genome of eight of the squamous cancers to look for chromosomal instability, and found no parts of chromosomes had become fused or swapped with other chromosomes, which are major hallmarks of chromosomal instability. In fact, these cancers seem to have less chromosomal instability than comparable squamous cancers that arise in people without short telomere syndromes, says Armanios.

Looking more closely at the immune systems of the 14 patients with squamous cancers, 12 had levels of T-cells that were several standard deviations below the median range for people.

In a related set of experiments with a group of mice genetically engineered to have short telomeres, the researchers found low quantities of cancer-fighting immune cells, similar to levels in people with short telomeres. Mice with short telomeres were not able to fight off implanted cancers long term nor could they recruit T-cells effectively to the tumor site.

Our data suggest people with short telomeres may have a lower incidence of most cancers with some cancers arising in a small subset, says Armanios, who adds that short telomeres may not destabilize peoples genomes but, in rare cases, affect the capacity of T-cells to expand and maintain their memory to fight cancer in the long-term.

Armanios says the findings will help physicians target cancer screening to high-risk individuals with short telomeres and avoid exposing them to excess immunosuppressive drugs known to increase their risk for infection.

In addition to Armanios and Schratz, other researchers contributing to the study are Diane Flasch, Wentao Yang and Jinghui Zhang from St. Jude Childrens Research Hospital; Robert Vonderheide from the University of Pennsylvania; and Christine Atik, Zoe Cosner, Amanda Blackford, Dustin Gable, Paz Vellanki, Zhimin Xiang, Valeriya Gaysinskaya and Lisa Rooper from Johns Hopkins.

Funding for the research was provided by the National Institutes of Health (R01CA225027, R01HL119476, P30CA006973, T32GM007309, T32CA009071, F32HL142207, R01CA229803), Gary Williams Foundation, S&R Foundation, the Commonwealth Foundation, Godrej Industries, the Harrington family, the ASH Scholar Award, the Dresner Foundation and the Turock Scholars Fund.

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Embryology

Can exercise help with Endometriosis? – EchoLive.ie

MARCH is Endometriosis Action Month, the annual event that aims to shine a spotlight on the gynaecological disease that affects one in 10 women.

The condition, where tissue similar to the lining of the womb grows in other places, such as the ovaries and fallopian tubes, can present itself in a number of ways.

Symptoms include chronic, sometimes debilitating pelvic pain, painful periods, painful bowel and bladder movements, painful sex, fatigue, and difficulty getting pregnant, saysFaye Farthing, head of campaigns and communications at Endometriosis UK (endometriosis-uk.org).

The cause of endometriosis hasnt been determined by researchers, theres no known cure, and it can be difficult to get a diagnosis due to a lack of awareness and understanding of symptoms.

Treatment and management of symptoms can include surgery, hormonal treatments and painkillers, said Farthing.

Endometriosis and exercise

For those who have received a diagnosis, navigating exercise and pain can be a challenge, but there is some evidence that movement can help alleviate painful symptoms.

Guidance from the European Society of Human Reproduction and Embryology (ESHRE, eshre.eu) makes what it calls a cautious recommendation that those with endometriosis should consider exercise, says Farthing.

Its not just the physical effects that make a difference when it comes to chronic pain.

Exercise can help improve symptoms for some women who have endometriosis, helping them feel better, both mentally and physically, says Amanda Place, personal trainer and founder of Sculptrition (sculptrition.com).

The mood-boosting effects from exercise is especially important.

While Abbie Watkins, personal trainer at OriGym (origympersonaltrainercourses.co.uk), explains: Exercise, regardless of intensity and duration, releases endorphins, which help us feel happier and can prolong periods of time where endometriosis sufferers feel pain-free.

Thats why we talk about runners high but you dont have to embark on a gruelling fitness regime to get those endorphins flowing.

Slow and steady

My first tip would be to take it slowly, making time to find the balance between what works for you and your fitness levels, and what helps with your endometriosis, Watkins continues.

Too quickly, and youll run the risk of burning yourself out, or worsening the pain you feel.

Yoga, pilates, or any other type of low to moderate impact workouts, such as swimming, brisk walking and cycling, are typically the best types of exercise to opt for when experiencing endometriosis-related symptoms, Place advises.

She also suggests incorporating exercises to strengthen the pelvic floor, such as heel slides and Kegel exercises.

Aim to exercise 30 to 60 minutes a day, up to five days a week.

However, the most important thing you can do is listen to your body.

Overexercising can worsen pain, so pace yourself, take frequent breaks, and gradually increase the intensity of your workouts.

Yoga can also help, Watkins says: Certain yoga poses, such as the happy baby, chair pose, or mountain pose, offer significant benefits for the pelvic floor.

Farthing agrees that no matter what activity you choose, listening to your body is key: If in doubt, you should ask your GP, or another medical professional, such as a gynaecologist or endometriosis nurse specialist.

Particularly if youve had surgery, she says: Its really important to be careful with physical activity when recovering from surgery, so make sure you get advice from health professionals.

For an additional boost, you could buddy up with a friend, attend an exercise class or join a sports team.

Fitness includes benefits for mental health, especially if there is a social aspect to exercise, Farthing adds.

And we know that those with endometriosis are more likely than others to have symptoms of mental ill health.

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Can exercise help with Endometriosis? - EchoLive.ie

Embryology

Fertility expert shares the seven things you need to know before freezing your eggs – The Mirror

Embryologist Cynthia Hudson encourages women to consider their fertility earlier to better prepare them for the future

With a growing number of women choosing to have children later on, they are increasingly finding themselves in a race against the biological clock to start a family.

For many women, egg freezing is a great way to preserve fertility if they are planning to have a family in the future, but not any time soon. The process involves collecting a woman's eggs, freezing them and thawing them later so they can be used in treatment.

While the thought of starting a family may seem like a distant idea for some, lead embryologist Cynthia Hudson at fertility tech company TMRW Life Sciences, says considering your fertility earlier can better prepare you for the future.

Cynthia said: If a woman is unsure about whether she wants children at the moment, she can freeze her eggs to give her more options for family building in the future. She may never need or want to use them, but sometimes having that 'insurance policy' can help to relieve stress and anxiety.

Speaking to the Mirror, the expert answered the most frequently asked questions about egg freezing. Heres everything you need to know:

She said: There is no one right answer to this question, however, the younger you are when you freeze your eggs, the better your chances are of having a successful pregnancy later.

The quality and quantity of a womans eggs decline with age in line with traditional IVF cycle success rates. What this means is if youre over 35 you'll need to bank more eggs to get the same chance of success as someone who froze them when they were under 35.

She added: All of these questions should be discussed with your fertility specialist to determine the options that give you the best chances of achieving your parenthood dreams.

The rules on how long you can store frozen eggs changed in the UK on July 1, 2022, increasing from 10 years to up to 55 years. The Human Fertilisation and Embryology Authority (HFEA) explained that for storage to lawfully continue you will need to renew your consent every 10 years.

This extended time period affords women the freedom to confidently freeze their eggs without the worry that they will need to use them within 10 years or else have to discard them, said Cynthia.

The expert highlighted: It is important to think of egg freezing as an insurance policy rather than a guarantee it helps you to preserve your fertility for longer and gives you options, but cannot promise success.

The fertility industry is regulated and licensed by the HFEA and information can be found on their website on the different treatment options available, as well as clinic ratings and reviews.

To date, only small numbers of women in the UK who have frozen their eggs have actually gone back to use them, so it's difficult to draw firm conclusions from this sample.

Universally though, those using frozen eggs during IVF cycles have pregnancy rates that correspond to the age of the egg when it was frozen, not the age of the person that received embryos created from those frozen eggs," informed Cynthia.

Not every egg will fertilise, not every fertilised egg will result in a viable embryo, and not every viable embryo will lead to a live birth.

She added: This is why its important to understand all of the data and options available to you your fertility specialist will be able to answer all of your questions and advise you accordingly.

According to the HFEA, the average cost of having your eggs collected and frozen in the UK is 3,350, with medication being approximately 500 to 1,500 on top of that. Storage costs and other treatment options are not included in this number.

The embryologist explained: That said, freezing your eggs will require an IVF cycle later, so these costs need to be considered as well. Definitely speak to your fertility specialist about all of this.

With something as precious as a womans future fertility at stake, choosing the right fertility clinic is important. The HFEA is responsible for licensing and inspecting UK fertility clinics and their website details how clinics have scored against their inspections. This can give you an indication of the success rates and patient ratings of a clinic.

Women may also want to inquire about the technology and equipment used by clinics to freeze and store eggs and embryos. The current standard of care relies on manual identification, tracking, and written record keeping. As the numbers of frozen specimens under management increase, this can put pressure on human abilities to maintain accurate inventories, she said.

TMRW Life Sciences is changing these processes by bringing an automated platform for specimen management, identification, and storage of frozen human eggs and embryos to the field.

The egg freezing process is very similar to anyone undergoing IVF treatment in that it requires a standard evaluation and workup, followed by an ovarian stimulation plan to produce multiple eggs.

Cynthia said: The differences start at this point, because instead of making embryos with a partner or donor sperm source and attempting to fall pregnant, the eggs will be frozen on the day they come out.

When youre ready to use them, which could be years on, is when youll need to consider the second phase of this process (IVF). In the meantime, making sure theyre safe and secure until that point in time is critical to your eventual success, so be sure you bring all of these questions to your fertility specialist.

It is important to remember there are also alternative paths to parenthood. These could include introducing donor eggs, sperm or embryos to your journey.

Cynthia explained: Donor conception is a great way to achieve your goals if youre not producing high quality or enough eggs of your own, if you are in a same sex relationship, or you have a high risk of passing on an inherited disease.

You may need to partner with a gestational carrier to bring your child to this world. Yet another approach to having a child is choosing to foster or adopt; there are many paths to parenthood, and there is no one right way to do it."

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Fertility expert shares the seven things you need to know before freezing your eggs - The Mirror