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Cell Biology

Sung to lead cancer institute; Bankston wins fellowship – ASBMB Today

Sung takes over at San Antonio cancer institute

Patrick Sung, a professor, interim department chair and associate dean for research at the University of Texas Health Science Center at San Antonio's Long School of Medicine, has taken on another leadership role there. On March 1, he became the new director of the Greehey Children's Cancer Research Institute. He succeeds interim director Manjeet Rao and former director Peter Houghton.

Patrick Sung

The institute, founded in 2004, is a group of 18 labs doing research focused on topics related to pediatric cancers, including cancer genomics, DNA repair, tumor biology and drug development. Research in Sungs lab, which is part of the institute, focuses on DNA damage repair. He studies homologous recombination as a mechanism for repairing double-stranded DNA breaks, focusing on the mechanism of the recombinase Rad51. His lab is known for recapitulating double-stranded DNA repair in vitro. Failure of such repair can lead to chromosomal rearrangements that drive the development of cancer; at the same time, cancer cells are unusually adept at repairing DNA damage. Several years ago, Sungs lab found that Rad51 interacts with the well-known BRCA tumor suppressor proteins, suggesting new insights into how BRCA proteins suppress tumor formation.

Sung earned his Doctor of Philosophy degree in biochemistry at the University of Oxford in 1985. He came to the U.S. for a postdoc at the University of Rochester. After starting his faculty career at the University of Texas Medical Branch in Galveston, he worked as an associate professor at UT Health San Antonio before taking a position at Yale in 2003, in the department of molecular biophysics and biochemistry, which he later chaired. He was recruited back to the University of Texas in 2019 as a professor.

Sung has been an associate editor of the Journal of Biological Chemistry since 2014. He also is on the editorial board of the journal Genes and Development and formerly served on the editorial board of the journal Molecular & Cellular Biology.

Adriana Bankston, a legislative analyst for the University of California, has received a 2022 fellowship from Advancing Research Impact in Society, or ARIS, a program supported by the National Science Foundation.

Adriana Bankston

This award, shared with the University of California, Irvine's Harinder Singh, will support a program for training in science policy. The project, titled "Developing the next generation workforce through science policy as a bridge between science and society," will use insights from a course that Bankston and Singh taught at Irvine to develop an educational toolkit for universities and to build a community of practice in science policy and advocacy.

Bankston received her Ph.D. in biochemistry and cell and developmental biology at Emory University and was a postdoctoral researcher at the University of Louisville before becoming a policy and advocacy fellow at the Society for Neuroscience. Today, in addition to her position at UC, she works on numerous initiatives as chief executive officer and managing publisher of the Journal of Science Policy and Governance, and as a research investigator with the STEM Advocacy Institute. In February, she was part of a panel discussion hosted by the National Academies of Science, Engineering and Medicine's strategic council for research excellence, integrity and trust. She is also an ASBMB Today contributor.

The Center for Advancing Research Impact in Society is a project to improve public engagement with science and diversify the research workforce. Its fellows, selected annually, work on projects that synthesize research to help scientists achieve these goals.

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Sung to lead cancer institute; Bankston wins fellowship - ASBMB Today

Cell Biology

‘We were so damn lucky to find this’: Tennesseans close to developing radiation exposure drug – Knoxville News Sentinel

Russian troops exposed to radiation, Chernobyl experts say

Thousands of enemy tanks and troops rumbled into Chernobyl during Russias invasion of Ukraine churning up highly contaminated soil.

Scott L. Hall, USA TODAY

Scientists in Tennessee are developing a promising drug they desperately hope will never be used.

Its a treatment that could rescue people from gastrointestinal acute radiation syndrome. In blunt terms, radiation poisoning.

"We were so damn lucky to find this mechanism that nature invented for us," said Dr. Gabor Tigyi,a cell biologist and cancer researcher at the University of Tennessee Health Science Center in Memphis. "We made a drug to harness it. .. It took about 20 years to figure out what we had in hand."

There is no drug on the market for the treatment of this illness. It's a weakness in our country's preparedness for nuclear accidents and attacks.

The drug is important locally, too. Much of the nations nuclear waste is processed in Tennessee. The state is home to many legacy nuclear sites, some of which date back to the World War II Manhattan Project.

More: Webb School of Knoxville dedicates new Governors Center for Innovation

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When the human body is exposed to radiation, high-energy particles penetrate cells and tissues to damage our DNA and cellular machinery. DNA damage is the reason why radiation exposure can induce cancers. Not all DNA damage repair occurs without error, and those errors can induce mutations that favor tumors.

When the body is exposed to very high levels of radiation for a brief period of time the kind of exposure that can happen in a nuclear accident the danger isnt necessarily cancer but loss of function in organs and tissues. Each tissue has different tolerances for radiation doses.

Two of the most sensitive tissues are bone marrow and intestinal tissue. Bone marrow is the nursery of red and white blood cells. Stem cells in the bone marrow constantly grow and divide to replace blood cells that expire.

"The lymphocytes in the blood and bone marrow, those are exquisitely sensitive," said Carol Iddins, director of theRadiation Emergency Assistance Center/Training Site in Oak Ridge. "They are arguably the most sensitive cells in our bodies so they're going to drop faster and harder."

But bone marrow damage from radiation already has treatments, and they are effective. Those drugs were developed for cancer patients undergoing radiation therapy.

"That was a low-hanging fruit, really," said Andrea DeCarlo-Cohen, director of the, Radiation and Nuclear Countermeasures Program at the National Institute for Allergy and Infectious Diseases. Because bone marrow complications kill much faster than other radiation complications, the drugs were prioritized, she said.

But no treatment existed for gastrointestinal cells.

"It's a much more complex injury," DeCarlo-Cohen said. "The stem cell biology of the GI tract is behind. ...It's just a much more complex structure."

The intestine is lined with a single layer of rapidly-diving cells. These cells grow upward into wavy, hair-like structures called villi. The stem cells and youngest cells are at the bottom. As cells age, they are pushed up the villi until they are shed into the intestine. Each intestinal cell lives for about four or five days before being shed.

That kind of cell turnover requires active adult stem cells. The intestine is full of them, constantly growing and dividing. When the intestine is hit by a high dose of radiation, it can damage the stem cells, causing them to self-destruct.

One of the ways the body prevents most cancersis a cellular self-destruct mechanism called apoptosis.

Tigyi'sdrug stimulates the DNA repair mechanism and slows down apoptosis. This buys some time for the intestinal stem cells to save themselves from radiation damage.

In tests on mice and monkeys, Tigyi's drug improved the survival rate after radiation exposure.

Tigyioriginally stumbled onto this mechanism while looking at platelets, the cell fragments your body uses to form blood clots. He found a short-lived signaling molecule, LPA,associated with wound repair.

"Our compound is modeled after this natural compound,"Tigyi said. "It promotes these mechanisms that lead to survival, regeneration and radiation protection."

If you can interrupt the self-destruct process long enough for the cells natural DNA repair mechanism to kick in, then you can potentially savestem cells and prevent catastrophic damage.

"The fundamental issue is enhancing DNA repair," Tigyi said. "Your cells are programmed such that if DNA damage is not repaired, the cell undergoes apoptosis and dies."

In other news: Blackberry Farm alum brings 'low and slow' barbecue to new East Tennessee restaurant

More: University of Tennessee's new out-of-state space research center launchesin Rocket City, Alabama

Dr. Shannon McCool was brought in to shepherd the drug process through FDA approvals. McCool is a graduate of UT's Health Science Center who has worked for large pharmaceutical operations like Eli Lilly and has experience navigating the regulatory landscape.

In 2000, the duo founded RxBio, a pharmaceutical company in Johnson City, toensure the drug was approved for treatment. The research wasin the final rounds of safety testing when the COVID-19 pandemic hit.

The pandemic didnt just make the research harder from a logistical standpoint.McCool said it becamedifficult to get funding.

"Nobody would give you the time of day," McCool said, referring to discussions with the Pentagon about defense-oriented medical funding."COVID-19 had sucked all the air out of the room."

A drug like this doesnt have to go through the standard FDA phased clinical trials because, of course, its not ethical to irradiate human beings.But itdoes have to go through extensive safety testing in large animal model systems. Thatcan be expensive.

Nowthere is potential space for the drug to get additional funding. Tigyi hopes that working with the Tennessee congressional delegation will help secure enough funding to begin passing the FDA's safety standards.

"We've been barely staying alive for the last several years," McCool said. "We estimate that we need $35 million, plus another 50-100 million on top of that to get everything done that we estimate the FDA will want us to do."

In an earlier version of this storyDr. Gabor Tigyi's name wasmisspelled. The error has been corrected in this version.

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'We were so damn lucky to find this': Tennesseans close to developing radiation exposure drug - Knoxville News Sentinel

Cell Biology

Retired Astronaut Wants to Grow Cannabinoids in Space – High Times

In the annals of phony viral images, the one of former Canadian astronaut Chris Hadfield holding a bag of weed while aboard the International Space Station is right up there.

The photo made the rounds in 2018, prompting a fact-check from the online watchdog Snopes.

In the original photo that was posted to Hadfields Twitter account in 2013, he is seen holding a bag of Easter Eggs.

The internet being the internet, that same image was manipulated years later and reposted by a Facebook page (ironically named Pictures in History), this time with the eggs replaced with ganja.

Not only is the image of Chris Hadfield holding a bag of marijuana fake, but its unlikely that any similar (but genuine) photographs of astronauts with drug paraphernalia exist, as NASA has been a drug-free workplace since at least the mid-1980s, Snopes said.

But the spurious image may have been somewhat prescient. Late last year, Hadfield joined the board of BioHarvest Sciences, a biotech firm involved in medicinal cannabis.

In an interview with Futurism that was published this week, Hadfield and BioHarvest CEO Ilan Sobel detailed how space might even be the perfect environment to produce out-of-this-world, medical-grade cannabinoids.

We see the potential ability for valuable minor cannabinoids to be grown at significantly higher quantities compared to its growth on Earth, Sobel told Futurism.

These unique compositions of full-spectrum cannabis could have significant value in providing more optimized treatment solutions for many palliative diseases where current pharma synthesized compounds are not delivering adequate solutions, he added.

But Hadfield told Futurism that cannabinoids are only one part of BioHarvests cultivation program, and what really drew him to the company was the scalability of the biotech platform, and how it can solve a lot of the agricultural problems we face in feeding 10 billion people.

As such, BioHarvest is focusing its efforts on providing future astronautsand humans back on the groundwith microgravity-enhanced nutrients, rather than a way to get high, Futurism reported.

Hadfield joined BioHarvests Board of Advisers in December, saying at the time that the companys proprietary platform technology has the potential to make a significant impact on the world as well as in bio-space science.

The company has built a world-class team of scientists, and I look forward to working with them, with my fellow advisors, to scale BioHarvests solution, Hadfield said in the announcement.

Sobel said at the time that Hadfields unparalleled experience will help marry our plant cellular biology expertise with space science.

He is a great addition to our advisory board at this phase of our growth, and hell help us in our drive to be a global biotech leader, Sobel said.

As for that infamous viral image, Hadfield told Futurism that toking in space might not be such a great idea.

On the space station, if theres an emergency, you are the fire department, he said. You cant have intoxicated yourself or inebriated yourself or whatever, just because if something goes wrong, then youll die.

He did leave open the possibility, however.

Once the population gets large enough, once you get to a stable enough situation, people are gonna want, you know, a drink, Hadfield told Futurism. People are gonna want some pot.

When it comes to cannabinoids and space, Hadfield and BioHarvest arent exactly going where no man has gone before.

In 2020, the ag biotech company Front Range Biosciences announced that it will be sending cell cultures of the hemp plant to the International Space Station on a resupply trip, Rolling Stone reported at the time, adding that the purpose of the project is to see whether or not these cells develop any genetic mutations in those conditions, and once they return, scientists will analyze their DNA to see if they have changed at all.

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Retired Astronaut Wants to Grow Cannabinoids in Space - High Times

Cell Biology

A team of UK researchers transform ageing research – NutraIngredients-usa.com

The Catalyst Reducing ImmuNe Ageing (CARINA) Network comprises more than 70 clinicians and researchers with compatible expertise in fields such as immunology, nutrition, and medicine.

CARINA is one of 11 networks fundedby the Medical Research Council (MRC) and Biotechnology and Biological Sciences Research Council (BBSRC)that aspire to transform ageing research in the UK.

The team of experts will identify priority areas for immunity and age research to advance the integrated understanding of the factors influencing the trajectory to an aged, compromised immune system and inspire new approaches to support ageing populations.

"The CARINA Network will facilitate large-scale collaboration between researchers from multiple disciplines who, for the first time, will work together to identify and better understand patterns and commonalities in the immunology of ageing, explains Professor Arne Akbar, Chair of CARINA Management Board.

As the ageing population grows, better understanding of immune mechanisms as we get older could help identify new methods to enhance quality of life and even improve life expectancy, say scientists.

Network member and chair of intestinal microbiome at the Technical University Munich, Professor Lindsay Hall, comments: It will be important to work with colleagues from a range of sectors to understand how further work in this area could be used to provide useful biomarkers of immune health.

Our immune system changes as we get older and responses to disease are unpredictable. Studies suggest that immunity declines with age, making it harder to fight off infections.

The COVID-19 pandemic has demonstrated the vulnerability of older people when confronted with a new pathogen, which can translate into severe outcomes for some, and highlights the utility of age-related research.

Professor Hall adds:We hope this new network will drive new interactions and new ways of thinking particularly around development of microbial and diet-based therapies that could also be used to boost beneficial immune responses, like after vaccination.

CARINA is supported by partners in industry and charities, as well as by public and patient groups.

TheBritish Society for Immunology (BSI) provides project management services for planning and delivery of important milestones, in addition to events support, communications expertise, and mediation of patient and public involvement (PPI).

Meanwhile, a Management Group, led by Chair Professor Akbar, formulates research strategies to ensure the Network facilitates a novel approach to ageing research. Professor Akbar is also Professor of Immunology at University College London, and President of the BSI.

Other members of the Management Group include: Professor Deborah Dunn-Walters (Professor of Immunology, University of Surrey); Professor Janet Lord (Professor of Immune Cell Biology, University of Birmingham); Dr Ed Chambers (Lecturer in Nutrition and Dietetics, Imperial College London), and Professor Neil Mabbott (Professor of Immunopathology, University of Edinburgh).

An independent Scientific Advisory Board of representatives from academia, clinicians, and public and patient groups has also been established to guide Network activity and make sure the research is sufficiently inclusive and interdisciplinary.

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A team of UK researchers transform ageing research - NutraIngredients-usa.com

Cell Biology

Dual delivery of BMP2 and IGF1 promotes cranial bone defect healing – EurekAlert

image:Journal brings together scientific and medical experts in the fields of biomedical engineering, material science, molecular and cellular biology, and genetic engineering. view more

Credit: Mary Ann Liebert, Inc., publishers

A new dual delivery system designed to sequentially release BMP2 and IGF1 in microparticles in an injectable hydrogel successfully healed an 8-mm cranial defect in rats. The study design and results are reported in the peer-reviewed journal Tissue Engineering, Part A. Click hereto read the article now.Cranial bone defects of a critical size cannot repair spontaneously, and affected patients ultimately required surgical reconstruction of the cranial bone. Experiments have shown that bone morphogenetic protein2 (BMP2)-laden hydrogel can promote cranial bone defect healing after implantation in rats. Insulin-like growth factor1 (GF1) is another growth fact that exerts a cell proliferation and differentiation effect on bone cells.

In this study, Yunzhi Peter Yang, PhD, from Stanford University School of Medicine, and coauthors, examined the sequential release of BMP2 followed by IGF1 in microparticles in injectable hydrogels in a rat model of cranial bone defect healing.

The investigators reported that microparticles containing BMP2 (2 g) or a combination of BMP2 (1 g) and IGF1 in the hydrogel successfully restored the 8-mm diameter cranial defect as early as 4 weeks after implantation. It suggests that supplemental IFG1 (1 g) to the lower dose of BMP2 (1 g) could be as effective as higher dose of BMP2 (2 g), state the investigators. Considering possible side effects of BMP2 in high doses, a supplemental IFG-1 may reduce the use of BMP2, which helps in minimizing the risk of causing side effect.

Dr. Yang and colleagues beautifully demonstrate the utility of a dual release microparticle system as an emerging technique for cranial bone regeneration.Further, their results show that the use of two potent growth factors in a sequential delivery system allows for a reduction in dose, potentially mediating off-target effects a critical advance in the field of tissue engineering, says Tissue Engineering Co-Editor-in-ChiefJohn P. Fisher, PhD, Fischell Family Distinguished Professor & Department Chair, and Director of the NIH Center for Engineering Complex Tissues at the University of Maryland.

About the JournalTissue Engineeringis an authoritative peer-reviewed journal published monthly online and in print in three parts: Part A, the flagship journal published 24 times per year; Part B: Reviews, published bimonthly, and Part C: Methods, published 12 times per year. Led by Co-Editors-in-ChiefAntonios G. Mikos, PhD, Louis Calder Professor at Rice University, Houston, TX, and John P. Fisher, PhD, Fischell Family Distinguished Professor & Department Chair, and Director of the NIH Center for Engineering Complex Tissues at the University of Maryland, the Journal brings together scientific and medical experts in the fields of biomedical engineering, material science, molecular and cellular biology, and genetic engineering. Leadership of Tissue Engineering Parts B (Reviews) and Part C (Methods) is provided by Katja Schenke-Layland, PhD, Eberhard Karls University, Tbingen and John A. Jansen, DDS, PhD, Radboud University, respectively. Complete tables of content and a sample issue may be viewed online at theTissue Engineering website. Tissue Engineering is the official journal of theTissue Engineering& Regenerative Medicine International Society (TERMIS). Complete tables of content and a sample issue may be viewed on theTissue Engineering website.

About the PublisherMary Ann Liebert, Inc., publishersis known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research. Its biotechnology trade magazine,GEN (Genetic Engineering & Biotechnology News), was the first in its field and is today the industrys most widely read publication worldwide. A complete list of the firms more than 100 journals, books, and newsmagazines is available on theMary Ann Liebert, Inc., publisherswebsite.

Experimental study

Animals

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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Dual delivery of BMP2 and IGF1 promotes cranial bone defect healing - EurekAlert

Cell Biology

Learning from RNA’s Mistakes Along the Way – University of Colorado Anschutz Medical Campus

Sujatha Jagannathan, PhD, chases RNA for a living and the pursuit often takes her in directions she didnt expect to go.

It turns out that the detours are the journeys reward.

Anytime nature breaks things, Jagannathan says, you can swoop in and understand exactly how the pathway works. Why is it broken? And what happens if you break a pathway like that?

Its the mistakes that provide the opportunity to learn, she says.

I study how mistakes in these molecules called RNA are handled by cells, basically, she says. We all have a genome in which genes are encoded. Its sort of like this big cookbook, where you have every recipe possible. Each cell in our body makes a subset of those genes that gives them their identity.

Messenger RNA, or mRNA, transfer information from the cookbook to other parts of the cell, where they are key ingredients to making proteins.

To end up running a laboratory focused on mRNA at the University of Colorado School of Medicine, Jagannathan herself took her own detour. I went to Duke to do my PhD in microbiology, and I came across this lab that did RNA biology and I said, That sounds cool, lets give it a shot, she says. And I fell in love.

Jagannathan had planned to study bacteria microscopic single-celled bugs that can sometimes make people sick but turned her attention to those microscopic messengers hauling the instructions for life itself.

Theres just something about the idea of this chancy and unstable molecule orchestrator thing, you know, she says. How it affects everything from how humans are made, embryogenesis, all the way to diseases and aging and this whole plethora of functions, just fascinated me. And I thought, Okay, studying bacteria was nice, but this is what Im going to do.

Jagannathan had completed a bachelors degree in industrial biotechnology at Anna University in Chennai, India, in 2006 before heading to Duke University, where she earned a PhD in cell biology.

I specifically studied how RNA molecules go to different places in the cell, she says. Because putting the same molecule in different parts of the cell can give it different properties, exactly the same molecule in different places has different properties. Its really amazing.

From Duke, Jagannathan went Fred Hutchinson Cancer Research Center in Seattle for a four-year postdoctoral fellowship.

I knew coming off of my PhD that I wanted training in computational biology, because thats where biology was heading, she says. I wanted to be able to do these high-throughput approaches, analyze my own data, really take advantage of computation as a tool to understand the intricacies of biology.

In Seattle, Jagannathan worked on research of facioscapulohumeral muscular dystrophy (FSHD), a debilitating disease that slowly consumes skeletal muscle in the face, scapula (shoulder blade), and humerus (upper arm).

Combining her interests in RNA biology and computational biology, Jagannathan collected data measuring RNA and protein levels in cells that express the protein DUX4. That protein induces changes in hundreds of genes that affect dozens of interconnected pathways. With so many connections, specific causes of FSHD are hard to discern. Her studies helped identify patterns for more targeted research.

Normally, this protein is expressed in early development, she says. But in people who have this disease, the protein turns on in this skeletal muscle, and turns on genes that should have no business being expressed in skeletal muscle.

Such research is a step-by-methodical-step process.

When you think of science, its sort of like climbing a mountain, she says. Every day, youre putting your head down, and youre just climbing. That can be hard, right? And then when you have a team of people that youre doing it with, you are cheerleading, helping, facilitating, seeing them go up the mountain too.

The reward is really when you can go to a height and you can see a new vista, something you didnt know existed, something thats going to now open up so many new opportunities. I think thats the joy. Seeing it myself, but also helping other people see it too.

For Jagannathan, the RNA Bioscience Initiative at the University of Colorado School of Medicine provided an opportunity to work in a community of scientists with similarly focused research.

I came to CU because of this group, she says. I had other offers, but this was the place that made me feel that as an RNA person, I couldnt be in a better place.

Jagannathan, an assistant professor of biochemistry and molecular genetics, and other RNA Bioscience Initiative scientists are clustered in offices and laboratories on the same floor of one of the research towers on the CU Anschutz Medical Campus.

If I just step out into the corridor, I can run into any colleague and I can ask, Hey, you know, I have this idea, what do you think? And they can shut it down or they can say, Heres another way of thinking about it, or heres the reagent I have, go do the experiment,or I can do the experiment for you. These are the opportunities of being here. Its the community, its just enabled science that I did not think I would be doing four years ago.

When the COVID pandemic disrupted operations for several months in 2020, scientists worked from home to review studies and analyze previously collected data. But getting back to the labs was a high priority. Jagannathan served on a working group to help the campus explore childcare opportunities so that working parents could return to campus sooner.

The kind of basic research conducted by the RNA Bioscience Initiative members is fundamental for future scientific advances. Jagannathan notes that vaccines for COVID-19 were developed quickly because of decades of research.

We wouldnt have a COVID vaccine if the basic science hadnt been done for the past 30 years, she says. There are people who say, Oh, this vaccine just came out of nowhere. No, it did not come out of nowhere. It came out of the work of basic scientists for decades. You have to have that foundation. You cant build therapies overnight like that if you dont have people putting in the time.

The dedication to knowledge is necessary, but not the sole purpose of the scientific endeavor, Jagannathan says.

It doesnt make sense for me to say, Heres the science I want to do, heres the person who can do that. Its more than that. Its really about who do I want to come out of the lab. What kind of scientists are we putting out into the world? Are they good citizens? Are they kind people? I want my lab to be a place that can produce really good quality scientists who go out and are a positive presence in the world.

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Learning from RNA's Mistakes Along the Way - University of Colorado Anschutz Medical Campus

Cell Biology

New insights about ‘bad news’ breast cancer mutation point to treatment opportunities – EurekAlert

image:Steffi Oesterreich, Ph.D., co-leader of the Cancer Biology Program at UPMC Hillman Cancer Center, professor in the University of Pittsburgh School of Medicine Department of Pharmacology & Chemical Biology, and co-director of the Womens Cancer Research Center, a collaboration between UPMC Hillman and Magee-Womens Research Institute. view more

Credit: UPMC

A mutated gene found in more than 20% to 30% of breast cancer recurrences may help tumors become more aggressive and promote metastasis, according to a pair of new studies that uncover mechanisms behind these processes and point to new therapy targets.

Were excited about this research because it addresses an important clinical problem: A huge number of deaths in breast cancer patients are the result of mutations in estrogen receptor genes, said senior author Steffi Oesterreich, Ph.D., co-leader of the Cancer Biology Program at UPMC Hillman Cancer Center and professor in the University of Pittsburgh School of Medicine Department of Pharmacology & Chemical Biology. Our study provides a deeper understanding of how these mutations contribute to disease progression and also identifies potential vulnerabilities, which we hope will lead to development of personalized treatment approaches.

More than 40,000 women die each year from breast cancer in the United States. About two-thirds of tumors express estrogen receptor genes. Hormone therapy can be very effective for these estrogen receptor-positive (ER+) tumors, but in about one-third of cases, the receptor becomes mutated and no longer responds to this treatment.

As a first step toward developing new therapies for these patients, the multi-institutional team led by Dr. Zheqi (Vaciry) Li, who was a postdoctoral associate in Oesterreichs lab, took a closer look at tumors harboring estrogen receptor gene ESR1 with a mutation at one of several hotspots in the genetic code.

In a new Cancer Research study, the researchers show that these hotspot mutations not only drive resistance to hormone therapy but also promote metastasis, helping breast cancer cells move to other parts of the body.

According to Oesterreich, ESR1 is a master regulator of several molecular pathways, including a type of interaction between cells called cell-cell attachment. When the researchers took liquid biopsies from patients with mutated ESR1, they found clusters of tumor cells circulating in the blood.

We think that this mutation makes tumor cells sticky, so they clump together, said Oesterreich, who is also co-director of the Womens Cancer Research Center, a collaboration between UPMC Hillman and Magee-Womens Research Institute. This is a novel finding and somewhat unexpected.

The researchers suspect that these sticky clumps of cells are transported throughout the blood and adhere to healthy tissues, promoting new tumors, or metastases, in other parts of the body.

This mutation is bad news for cancer prognosis, but the good news is that there are drugs that target cell-cell attachment, said Oesterreich. We hope that this study lays the foundation to test drugs that prevent or treat metastatic breast cancer driven by estrogen receptor mutations.

In the second study, published today in Nature Communications, the researchers found that tumors with ESR1 mutations also had high expression of so-called basal features, which make breast cancers aggressive and difficult to treat.

But this study also offered a silver lining. Mutant tumors had high expression of genes associated with tumor infiltration by macrophages, a type of immune cell that cleans up dead cells and destroys bacteria and other pathogens.

Previously, it was thought that ER+ tumors are cold, or impenetrable by immune cells, meaning that they dont respond to immunotherapy, explained Oesterreich. But these findings give us a potential new target for patients with the ESR1 mutant breast cancer: Targeting macrophages could kill the tumor.

In ongoing work, Oesterreich and her team seek to confirm immune infiltration in ESR1 mutant tumors collected at other research centers. They are also collaborating with investigators from other institutions to test whether cell-cell attachment involved in metastasis can be blocked with drugs.

Additional authors on the Cancer Research and Nature Communications studies are listed in the papers.

Nature Communications

Experimental study

Human tissue samples

ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

19-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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New insights about 'bad news' breast cancer mutation point to treatment opportunities - EurekAlert

Physiology

Trevena Announces Results from Respiratory Physiology Study of Head-to-Head Comparison of OLINVYK and IV Morphine in Elderly/Overweight Subjects -…

Trevena Inc.

OLINVYK showed a statistically significant reduced impact on respiratory function compared to IV morphine, among elderly/overweight subjects

Data replicate observations previously seen in a comparative study of respiratory physiology in younger subjects with OLINVYK and IV morphine

CHESTERBROOK, Pa., April 20, 2022 (GLOBE NEWSWIRE) -- Trevena, Inc. (Nasdaq: TRVN), a biopharmaceutical company focused on the development and commercialization of novel medicines for patients with central nervous system (CNS) disorders, today announced results from its double blinded, crossover study evaluating OLINVYK (oliceridine) injection for the management of acute pain, in elderly/overweight. This study builds on the collaborative work with Dr. Albert Dahan and his research team at Leiden University Medical Center (LUMC).

We are very pleased with the results of our study, which replicate earlier results reported in younger subjects, said Dr. Albert Dahan, Professor of Anesthesiology at Leiden University Medical Center, These data suggest that OLINVYK, a new chemical entity, may offer a more favorable respiratory safety profile when compared to IV morphine.

Dr. Dahans team compared the analgesic and respiratory effects of two doses of OLINVYK (0.5mg and 2.0mg) and morphine (2.0mg and 8.0mg) administered intravenously in a population of elderly individuals (age range 56 to 87 years, mean age = 71.2) across a range of body weight (BMI range from 20 to 34 kg/m2, mean BMI= 26.3). Subjects were tested on 4 occasions and randomized by drug and dose. On each visit, the ventilatory response to inhaled carbon dioxide was measured to evaluate the potential effect of the drug on the brain respiratory centers. Elderly and overweight patients are known to be at higher risk of respiratory depression with the use of opioid medications. This study hypothesized that, at similar levels of analgesia, there would be a reduced impact on respiratory function with OLINVYK compared to IV morphine. The primary endpoint of the study was ventilatory rate at an extrapolated PCO2 of 55 mmHg (VE55).

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Key Findings

Both OLINVYK and IV morphine achieved comparable levels of pain relief. However, a statistically significantly reduced impact on respiratory function was observed in patients treated with OLINVYK compared to IV morphine, as measured by the mean respiratory ventilation profiles over time (P < 0.0001).

In contrast to the lower dose of IV morphine, very little impact on respiratory function was observed with the lower dose of OLINVYK.

At the higher dose of both drugs studied, less respiratory depression over the 6 h measurement period was observed with OLINVYK. The peak level was lower for OLINVYK compared to morphine, though this difference was not statistically significant (P > 0.05). In addition, in contrast to morphine, respiratory function at the higher dose of OLINVYK rapidly returned toward baseline from 3 hours onward (all time points P < 0.05 in pairwise comparison).

The data replicate the results from a previously reported study in younger subjects.

Comparing the sensitivity of the impact on respiratory function from the earlier study and the results from the current study suggests that there is a nearly identical impact on respiratory function with OLINVYK in the younger and elderly age groups, while IV morphine data suggests an increase in impact in the elderly compared to the younger subjects.

We believe these data from Dr. Dahans study team are important. They replicate the results from an earlier study reported by Trevena in younger subjects using a similar methodology, and they extend our knowledge to patients who are at higher risk for the development of respiratory depression with the use of opioids, namely elderly and overweight patients, said Mark A. Demitrack, M.D., Senior Vice President and Chief Medical Officer of Trevena. As with all opioids, serious, life-threatening, or fatal respiratory depression may occur in patients treated with OLINVYK. We look forward to seeing further analysis of this data by Dr. Dahans team and working with him to see these results reported to the wider scientific community and submitted for publication in the near future.

About OLINVYK (oliceridine) injection

OLINVYK is a new chemical entity approved by the FDA in August 2020. OLINVYK contains oliceridine, an opioid, which is a Schedule II controlled substance with a high potential for abuse similar to other opioids. It is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. OLINVYK is available in 1 mg/1 mL and 2 mg/2 mL single-dose vials, and a 30 mg/30 mL single-patient-use vial for patient-controlled analgesia (PCA). Approved PCA doses are 0.35 mg and 0.5 mg and doses greater than 3 mg should not be administered. The cumulative daily dose should not exceed 27 mg. Please see Important Safety Information, including the BOXED WARNING, and full prescribing information at http://www.OLINVYK.com.

IMPORTANT SAFETY INFORMATIONWARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CENTRAL NERVOUS SYSTEM (CNS) DEPRESSANTS

ADDICTION, ABUSE, AND MISUSE OLINVYK exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patients risk before prescribing OLINVYK, and monitor all patients regularly for the development of behaviors or conditions.

LIFE-THREATENING RESPIRATORY DEPRESSION Serious, life-threatening, or fatal respiratory depression may occur with use of OLINVYK. Monitor for respiratory depression, especially during initiation of OLINVYK or following a dose increase.

NEONATAL OPIOID WITHDRAWAL SYNDROME Prolonged use of OLINVYK during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

RISK FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

INDICATIONS AND USAGEOLINVYK is an opioid agonist indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate.Limitations of UseBecause of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve OLINVYK for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

Have not been tolerated, or are not expected to be tolerated

Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

The cumulative total daily dose should not exceed 27 mg, as total daily doses greater than 27 mg may increase the risk for QTc interval prolongation.CONTRAINDICATIONSOLINVYK is contraindicated in patients with:

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected gastrointestinal obstruction, including paralytic ileus

Known hypersensitivity to oliceridine (e.g., anaphylaxis)

WARNINGS AND PRECAUTIONS

OLINVYK contains oliceridine, a Schedule II controlled substance, that exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OLINVYK. Assess risk, counsel, and monitor all patients receiving opioids.

Serious, life-threatening respiratory depression has been reported with the use of opioids, even when used as recommended, especially in patients with chronic pulmonary disease, or in elderly, cachectic and debilitated patients. The risk is greatest during initiation of OLINVYK therapy, following a dose increase, or when used with other drugs that depress respiration. Proper dosing of OLINVYK is essential, especially when converting patients from another opioid product to avoid overdose. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patients clinical status.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia with risk increasing in a dose-dependent fashion. In patients who present with CSA, consider decreasing the dose of opioid using best practices for opioid taper.

Prolonged use of opioids during pregnancy can result in withdrawal in the neonate that may be life-threatening. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using OLINVYK for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OLINVYK with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, or alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate, prescribe the lowest effective dose, and minimize the duration.

OLINVYK was shown to have mild QTc interval prolongation in thorough QT studies where patients were dosed up to 27 mg. Total cumulative daily doses exceeding 27 mg per day were not studied and may increase the risk for QTc interval prolongation. Therefore, the cumulative total daily dose of OLINVYK should not exceed 27 mg.

Increased plasma concentrations of OLINVYK may occur in patients with decreased Cytochrome P450 (CYP) 2D6 function or normal metabolizers taking moderate or strong CYP2D6 inhibitors; also in patients taking a moderate or strong CYP3A4 inhibitor, in patients with decreased CYP2D6 function who are also receiving a moderate or strong CYP3A4 inhibitor, or with discontinuation of a CYP3A4 inducer. These patients may require less frequent dosing and should be closely monitored for respiratory depression and sedation at frequent intervals. Concomitant use of OLINVYK with CYP3A4 inducers or discontinuation of a moderate or strong CYP3A4 inhibitor can lower the expected concentration, which may decrease efficacy, and may require supplemental doses.

Cases of adrenal insufficiency have been reported with opioid use (usually greater than one month). Presentation and symptoms may be nonspecific and include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If confirmed, treat with physiologic replacement doses of corticosteroids and wean patient from the opioid.

OLINVYK may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension. In patients with circulatory shock, avoid the use of OLINVYK as it may cause vasodilation that can further reduce cardiac output and blood pressure.

Avoid the use of OLINVYK in patients with impaired consciousness or coma. OLINVYK should be used with caution in patients who may be susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or brain tumors, as a reduction in respiratory drive and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy.

As with all opioids, OLINVYK may cause spasm of the sphincter of Oddi, and may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

OLINVYK may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in vulnerable patients. Monitor patients with a history of seizure disorders for worsened seizure control.

Do not abruptly discontinue OLINVYK in a patient physically dependent on opioids. Gradually taper the dosage to avoid a withdrawal syndrome and return of pain. Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving OLINVYK, as they may reduce the analgesic effect and/or precipitate withdrawal symptoms.

OLINVYK may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Although self-administration of opioids by patient-controlled analgesia (PCA) may allow each patient to individually titrate to an acceptable level of analgesia, PCA administration has resulted in adverse outcomes and episodes of respiratory depression. Health care providers and family members monitoring patients receiving PCA analgesia should be instructed in the need for appropriate monitoring for excessive sedation, respiratory depression, or other adverse effects of opioid medications.

ADVERSE REACTIONSAdverse reactions are described in greater detail in the Prescribing Information.The most common (incidence 10%) adverse reactions in Phase 3 controlled clinical trials were nausea, vomiting, dizziness, headache, constipation, pruritus, and hypoxia.MEDICAL INFORMATIONFor medical inquiries or to report an adverse event, other safety-related information or product complaints for a company product, please contact the Trevena Medical Information Contact Center at 1-844-465-4686 or email MedInfo@Trevena.com.You are encouraged to report suspected adverse events of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088.Please see Full Prescribing Information, including Boxed Warning.

About Trevena

Trevena, Inc. is a biopharmaceutical company focused on the development and commercialization of innovative medicines for patients with CNS disorders. The Company has one approved product in the United States, OLINVYK (oliceridine) injection, indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. The Companys novel pipeline is based on Nobel Prize winning research and includes four differentiated investigational drug candidates: TRV045 for diabetic neuropathic pain and epilepsy, TRV027 for acute respiratory distress syndrome and abnormal blood clotting in COVID-19 patients, TRV250 for the acute treatment of migraine and TRV734 for maintenance treatment of opioid use disorder.

For more information, please visit http://www.Trevena.com

Forward-Looking Statements

Any statements in this press release about future expectations, plans and prospects for the Company, including statements about the Companys strategy, future operations, clinical development and trials of its therapeutic candidates, plans for potential future product candidates and other statements containing the words anticipate, believe, estimate, expect, intend, may, plan, predict, project, suggest, target, potential, will, would, could, should, continue, and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: the status, timing, costs, results and interpretation of the Companys clinical trials or any future trials of any of the Companys investigational drug candidates; the uncertainties inherent in conducting clinical trials; expectations for regulatory interactions, submissions and approvals, including the Companys assessment of discussions with FDA; available funding; uncertainties related to the Companys intellectual property; uncertainties related to the ongoing COVID-19 pandemic, other matters that could affect the availability or commercial potential of the Companys therapeutic candidates and approved product; and other factors discussed in the Risk Factors set forth in the Companys Annual Report on Form 10-K and Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings the Company makes with the SEC from time to time. In addition, the forward-looking statements included in this press release represent the Companys views only as of the date hereof. The Company anticipates that subsequent events and developments may cause the Companys views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, except as may be required by law.

For more information, please contact:

Investor Contact:

Dan FerryManaging DirectorLifeSci Advisors, LLCdaniel@lifesciadvisors.com(617) 430-7576

PR & Media Contact:

Sasha BennettAssociate Vice PresidentClyde GroupSasha.Bennett@clydegroup.com(239) 248-3409

Company Contact:

Bob YoderSVP and Chief Business OfficerTrevena, Inc.(610) 354-8840

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Trevena Announces Results from Respiratory Physiology Study of Head-to-Head Comparison of OLINVYK and IV Morphine in Elderly/Overweight Subjects -...

Physiology

PODCAST: Field Atlas Helps to Explore Career Options – Inside INdiana Business

Even though Hanover College senior Baylee Dwenger was in 4-H and FFA while growing up, her collegiate path steered her away from agriculture. Shes earning a degree in kinesiology and physiology, which seems far removed from the farm. Still, as an intern with AgriNovus Indianas Field Atlas ambassador program, she sees vast opportunities in the agbioscience sector.

During this weeks Ag+Bio+Science podcast presented by AgriNovus, Dwenger explained the correlation.

I just found the diversity within agbiosciences to be so surprising. And then how quickly its developing, Dwenger explained to Inside INdiana Business and podcast host Gerry Dick. Its crazy how, a few years ago, the technology we have now didnt even exist. So just thinking about how quickly its developing is great to me.

The Field Atlas is an online career exploration platform that enables students to explore agbioscience careers through online talent assessments, videos and profiles. The resource helps young job seekers and college students to identify jobs and companies that align with their personal and professional interests.

Sriya Nagubani, a sophomore studying pharmaceutical science at Purdue University, also served as an ambassador during the spring semester.

I didnt know much about the agbioscience sector at all. But once I started being an ambassador, I learned how up and coming it was, said Nagubani. I can see how fast its growing and how inclusive it is. There are many majors that can be a part of it.

Dwenger and Nagubani agree the Field Atlas is a perfect tool to help steer high school and college students towards the abundant job choices in Indianas agbioscience sector.

The new Ag+Bio+Science podcast comes out Monday morning. Click here to learn more. To access the full line-up of Inside INdiana Business podcasts, click here.

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PODCAST: Field Atlas Helps to Explore Career Options - Inside INdiana Business

Physiology

Cermaq’s land-based lead to take up academic role – The Fish Site

He will teach bachelor and master students and eventually also supervise doctoral students. This will also involve developing courses on continuing education in aquaculture technology, especially with a focus on RAS/post-smolt. The courses will be open to all fish farming companies and others in the region. The long-term goal is also to initiate various research collaborations with external actors.

We are very pleased to have Bendik Fyhn Terjesen on the team in a professor II position, said Dean Mette Srensen in a press release.

Terjesen is a very experienced aquaculture scientist with a broad experience within recirculation and postsmolt production. We want to use his knowledge and experience towards existing and new courses aimed at both campus students and in continuing and further education courses aimed at the aquaculture industry. We also hope that the collaboration will contribute to the development of new knowledge through joint research projects with the aquaculture industry, added Srensen.

Terjesen has an extensive research career focusing on fish physiology and aquaculture technology and he made his first experiments in water recirculating aquaculture systems (RAS) in 1993 at Wageningen University. He led the construction of the Nofima Center for Recirculation in Aquaculture and the start-up of CtrlAQUA, a center for research-based innovation in aquaculture in closed systems, before joining Cermaq.

Aquaculture is an increasingly important source of safe, nutritious, and sustainable seafood for people worldwide. Globally, aquaculture production must double by 2030 to keep pace with demand. These increases in demand for aquaculture products, food security considerations, and job creation have generated an increased need for skilled workers.

Discover how you can be part of this rapidly expanding industry.

This is a recognition of Bendik as one of the persons with most technology expertise in the industry. Sharing knowledge through collaboration with Nord University is completely in line with Cermaq's knowledge- and research-based approach. We are confident that this will be a good cooperation for both parties and congratulate Terjesen on his appointment," said Erlend Reiten, chief transformation officer at Cermaq Group.

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Cermaq's land-based lead to take up academic role - The Fish Site