New USC/Children’s Hospital Los Angeles lab to accelerate next-gen cell therapy

Published January 27, 2023

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New USC/CHLA cGMP Lab opens to accelerate next-generation cell therapy

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New USC/CHLA cGMP Lab opens to accelerate next-generation cell therapy

A new laboratory designed to advance early-stage research into lifesaving, commercially viable therapies was celebrated on the USC Health Sciences Campus Tuesday night.

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Housed at the USC Norris Comprehensive Cancer Center, the USC/CHLA cGMP Laboratory will manufacture cell and gene therapies under the Food and Drug Administration’s good manufacturing practice (cGMP) standards.

Therapies developed in the lab could one day be used to treat diseases such as arthritis, blindness and diabetes.

The 3,184-square-foot facility offers cleanrooms, laboratory space, cryostorage and state-of-the-art equipment for manufacturing and analytical testing. It was launched through a partnership between Children’s Hospital Los Angeles, Keck Medicine of USC and the Keck School of Medicine of USC.

The lab’s collaborative structure, broad expertise, specialized resources and regulatory knowledge will help accelerate big ideas and positive “disruption” to health care, said USC President Carol L. Folt, PhD.

“Effective partnerships can facilitate these breakthroughs while also supporting the steady, incremental and absolutely critical advancements” necessary to move an idea from lab to bedside, Folt said. “Billions of lives across the world could be changed by this work.”

Keck School of Medicine Dean Carolyn Meltzer, PhD, who began her position in March 2022, praised the countless hours teams spent bringing the idea to life.

“I came here because this institution really embodies interdisciplinary collaboration to solve the tough problems,” Meltzer said. “And this is a moment where we’re well positioned for disruptive growth and impact, which is really what’s most meaningful.”

The partnership demonstrates continued “representation of what world-class organizations can do working together,” said Paul Viviano, president and chief executive officer of CHLA, noting that his institution and USC have maintained an affiliation since 1932. “This magnificent center is a major step forward.”

The lab is part of a larger effort — the USC/CHLA Cell Therapy Program — to advance the science and translation of cell therapies at both institutions. (The program is tied to the USC+CHLA Alpha Clinic, which in November 2022 was awarded a five-year, $8 million grant from the California Institute for Regenerative Medicine.)

This effort marks continued momentum for expanding precision medicine. The cGMP lab’s multidisciplinary teams will work to further leverage the power of modified cells — as seen in CAR T-cell therapy, which reengineers patients’ immune cells to fight their own blood cancers — and apply them in new ways.

“The great thing about cell therapy is that patients are not passive receiving treatment; they are active participants,” said Mohamed Abou-el-Enein, MD, PhD, MSPH, executive director of the USC/CHLA Cell Therapy Program and director of the new cGMP lab.

The facility, he added, is “the missing puzzle piece that can enable us to bring homegrown discoveries to the clinic and to our patients.”

Abou-el-Enein expects the lab to serve 200 patients annually and partner with leading biotech companies. He also intends for it to help train a new generation of scientists and to prioritize pediatric and East Los Angeles patient populations.

Housing multiple parts of the development process under one roof offers a distinct advantage for researchers and patients, said Rod Hanners, chief executive officer of Keck Medicine.

“Cell-based therapies represent a quantum change in medical treatments,” Hanners said. “The establishment of the Translational Cell Therapy program between Keck Medicine of USC, Keck School of Medicine of USC and Children’s Hospital of Los Angeles, including the new cGMP facility, provides the collaboration, expertise and infrastructure to take new therapies and move them into clinical trials — all with the promise of curing diseases that affect our patient population.”

— Kevin Joy

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Americans don’t know what’s a healthy blood pressure — and that’s a problem

Published January 26, 2023

8120 https://healthpolicy.usc.edu/article/false-confidence-in-blood-pressure-knowledge-undermines-intentions-to-seek-care/
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False Confidence in Blood Pressure Knowledge Undermines Intentions to Seek Care

Most Americans don’t know the meaning of 120/80 mm Hg, but think they do — and that’s a potential problem for their health.

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Nearly half of adults in the U.S. have high blood pressure (hypertension). In the long run, high blood pressure damages blood vessels, increases risk of heart failure, and leads to other poor health outcomes, especially in patients with additional conditions such as heart disease, kidney disease and diabetes. High blood pressure is more common as we get older, and a majority of people will develop blood pressure in their lifetime.

Yet, almost two-thirds of adults do not know the upper thresholds for normal or healthy blood pressure, according to a survey a new USC study published this week in the journal Medical Decision Making.

“High blood pressure usually has no symptoms,” said Wandi Bruine de Bruin , who co-directs the Behavioral Sciences program at the USC Schaeffer Center for Health Policy & Economics and is provost professor of public policy, psychology and behavioral sciences at the USC Price School of Public Policy. “So it is important to have your blood pressure tested, and to take action if it’s too high.”

While most survey participants did not correctly identify the threshold for healthy blood pressure, Bruine de Bruin and her team found that the majority were overly confident in their knowledge of blood pressure readings – and this false sense of confidence may be undermining their intentions to seek care for stage 1 hypertension.

What blood pressure numbers mean and when to seek care
Blood pressure is measured with two numbers. The top number, called systolic blood pressure, measures the pressure in our arteries when our hearts beat. The second number is called diastolic blood pressure and measures the pressure in our arteries when our hearts are resting between beats.

According to the American Heart Association, there are five blood pressure (BP) categories:

Table explaining blood pressure categories
The American Heart Association recommends that everyone with stage 1 hypertension talk to their doctor about making lifestyle changes, including eating a low-sodium diet, limiting alcohol use, being more physically active, maintaining a healthy weight, managing stress and quitting smoking. Medication is recommended for people with stage 2 hypertension and for some people with stage 1 hypertension, including those who also have heart disease, kidney disease or diabetes.

Confidence outpaces knowledge of what constitutes normal/healthy blood pressure
Bruine de Bruin and colleagues surveyed 6,592 U.S. adults, including 1,342 who had hypertension without comorbidities (heart disease, kidney disease, and diabetes) and 795 who had hypertension with comorbidities. They assessed whether survey participants could identify the threshold for normal/healthy blood pressure as well as their confidence in understanding blood pressure numbers.

Among the whole sample, 64% of participants expressed confidence in their understanding of blood pressure numbers but only 36% stated that 120/80 mm Hg was the upper threshold for normal/healthy blood pressure. When counting 120-130/80 mm Hg as correct, it was 39%.

Participants with high blood pressure without comorbidities were also more likely to be confident (78%) than knowledgeable (47%), when counting 120-130/80 mm Hg as correct. The same was true for participants who had high blood pressure with comorbidities who were slightly more confident (81%) but less knowledgeable (40%).

The researchers suggest that this false confidence may stem from repeated exposure to a topic. “We tend to feel more confident about topics that are more familiar. And blood pressure feels like a familiar topic because it gets measured at pretty much every healthcare visit,” says Bruine de Bruin. “But if these blood pressure measurements are not explained well or at all, we may develop false confidence. And that false confidence makes is feel that we know when to seek care, even when we don’t.”

Indeed, the researchers find that this false confidence in understanding blood pressure readings may undermine intentions to seek care. Survey participants who were confident were more likely to express intentions to act on stage 2 hypertension readings, but less likely to express intentions to act on stage 1 readings compared to those who were not confident.

“Identifying, treating, and controlling high blood pressure is a major clinical and public health challenge,” says coauthor Mark Huffman, professor of Medicine at Washington University in St. Louis. “We know that the earlier patients seek and receive treatment, the better and easier it is to control their blood pressure.”

Every doctor’s visit is an opportunity to talk about blood pressure
“Blood pressure is measured every time we go to the doctor as well as the dentist and other medical offices,” said Bruine de Bruin. “But knowledge about what these blood pressure numbers mean is not being transferred from the provider to the patient.”

It’s not clear why doctors skip opportunities to talk about managing high blood pressure. Possibly, doctors are desensitized to seeing stage 1 hypertension. High pressure is very common among adults across the U.S. Some people also have elevated blood pressure readings due to the stress or anxiety of being at a doctor’s office, which may lead doctors to take no action after seeing a high blood pressure reading.

But lowering blood pressure can help people stay healthy. In fact, a recent study showed that lowering systolic blood pressure by 5 mm Hg through medication reduces the risk of major cardiovascular events by 10%. Providing patients with information about blood pressure levels and behaviors and treatments they can do is an easy way to improve health, explained the researchers.

In addition to Bruine de Bruin and Huffman, Yasmina Okan (Pompeu Fabra University and Centre for Decision Research, Leeds University) and Tamara Krishnamurti (Center for Research on Health Care, University of Pittsburgh) coauthored the study. The survey was administered through the Understanding America Study at the USC Dornsife Center for Economic and Social Research.

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Social work researchers examine the health impacts of U.S. immigration policy

Published January 25, 2023

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Social work researchers examine the health impacts of U.S. immigration policy

Deporting immigrants to countries where they never lived is causing mental and physical health disparities for individuals and families.
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Immigration is one of the most controversial social and political issues in American life. Yet little attention is given to the aftermath of U.S. immigration policies or the immigrant Americans who are deported back to their country of origin. What is the resulting impact on mental and physical health disparities, both individually and at the societal level? This question is at the heart of groundbreaking research by scholars at the USC Suzanne Dworak-Peck School of Social Work.

Alice Cepeda, associate professor, and Avelardo Valdez, the Cleofas and Victor Ramirez Professor of Practice, Policy, Research and Advocacy for the Latino Population, have been studying disparities in health among deported Americans in Mexico City. They recently presented their important findings in a private audience with Ken Salazar, the United States Ambassador to Mexico, in hopes of expanding recognition for the impact current U.S. immigration policy is having on the lives of individuals and families.

“There are almost half a million deportees in Mexico City that are Americans,” Valdez said. “If you talk to these people, it’s like talking to any other U.S. citizen. Some of them have never even been to Mexico, have never even thought of going back, and suddenly find themselves in this strange country, separated and alienated from their families.”

Valdez and Cepeda have been working together to illuminate social and public health issues around Mexican American immigration and other factors for over 20 years. Their latest study funded by the National Institutes of Health – Disparities in Health among Floating Immigrant Populations – examines the health impacts of the U.S. immigration system. This study interviews recent immigrants in Los Angeles and deported Americans in Mexico City in order to identify mechanisms by which immigration processes expose individuals to distinct environments, increase susceptibility to risk behaviors and contribute to mental and physical health disparities, infectious diseases and alcohol/drug dependence. “Our goal with this research is to reframe immigration, not as a threat to public health, but instead recognizing immigrants’ special vulnerabilities from a human rights perspective,” Cepeda said. “The migration processes are something we really need to think about in terms of the health of these deported Americans, including mental health and substance use.”

Criminalizing the immigrant experience

When most people think of immigrants from Mexico to America they picture rural agricultural workers coming to work on farms in border states. However, many Mexican migrants to the United States today are from urban areas, and bound for major cities such as Los Angeles, Chicago or Atlanta to work in service sector jobs. Also in contrast to common wisdom, immigration from Mexico has actually decreased significantly in recent years, with 2 million fewer total unauthorized immigrants from Mexico living in the U.S. in 2017 than a decade earlier. This is attributable in part to a significant increase in deportations as a result of changes in immigration policy and the passage of laws specifically targeting immigrants. In 1996, the passage of the U.S. Illegal Reform and Immigrant Responsibility Act began the era of a deportation-carceral system that criminalizes immigrants, militarizes the border and removes long-term immigrants from the interior of the U.S. This law expanded the list of “deplorable” crimes that warranted deportation to include common misdemeanors such as identification or tax fraud, and making unauthorized re-entry into the U.S. a felony. In 2003, Immigration and Customs Enforcement (ICE) was created and expanded into the interior of the U.S., not just border areas, enlisting local law enforcement to apprehend unauthorized immigrants. Currently, immigration offenses are the most common federal crime, surpassing drug-related crime.

Many of these laws overwhelmingly target immigrants commonly known as “dreamers,” who came to the U.S. as children and might otherwise qualify for the Deferred Action for Childhood Arrivals (DACA) program to stay in the U.S. Because any criminal history, even misdemeanors, violates the DACA morality clause, these laws have the net effect of criminalizing immigration. For this reason, Cepeda and Valdez often refer to the deported Americans in Mexico City as the “other dreamers.” These deportees also create a new form of family separation. Among the deported Americans Cepeda and Valdez have surveyed in their study,45% report they left behind one or more children in the U.S., many of them U.S. citizens, disrupting the family’s primary financial support and creating tremendous anxiety and stress across the family.

One of the men Cepeda and Valdez interviewed personifies this dynamic. A 36-year-old married man with several children, residing in Dallas and earning a living as a contractor with six employees, was pulled over for a minor traffic infraction. Due to this immigration status, he was deported to Mexico, a place he had not been for over twenty years. His wife and children were suddenly left with no financial support and his employees without jobs. In an effort to keep his family together, he tried moving his wife and children to Mexico, but they were unable to acclimate to the social systems and language, eventually returning to the U.S. Now, his wife visits him occasionally in Mexico, but the children, who feel uncomfortable in Mexico, only communicate with their father by phone.

“Like they deported us to a war zone”

Many of these deported Americans do not remember Mexico or even speak Spanish. Suddenly they find themselves in a country with an unfamiliar system, struggling to survive, and the physical and emotional stresses of this journey taking a significant toll.

“This is a population that is dealing with very high, severe mental health issues and anxiety, distress, ecological distress,” Cepeda said. “We really wanted to look at how these distinct immigration experiences contribute to these outcomes. It’s not just the immigration itself, it’s the transit to the destination, the interception, and then now coming back.”

Valdez says that most of the people who are deported to Mexico City have no family ties at all in the area. They are just thrown into the city and then have to find a place to live and a job, with almost no support from the U.S. or Mexico.

“It’s like they deported us to a war zone, one we don’t know anything about,” said one 25-year-old deported American interviewed for the study who came to the U.S. at three years old and lived in Indiana until being returned to Mexico in 2018. “I grew up in the States all my life and they deport me when I’m an adult to someplace where I don’t know how to file my taxes, get a job or get my ID. The only option you’re giving us is to commit more crimes, because we don’t know what to do.”

Valdez and Cepeda anticipate their study will stimulate discussion and lead to the implementation of policies and programs by both the U.S. and Mexico governments that address these inequities in mental and health conditions for this population.

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Discoveries help bone marrow transplant recipients

Published January 17, 2023

8099 https://stemcell.keck.usc.edu/why-multipotent-progenitor-cells-matter/
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Why multipotent progenitor cells matter for patients receiving bone marrow transplants
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When patients receive bone marrow transplants, they are infused with complex admixtures of many different cell types with the power to regenerate their blood and immune systems. In a new study in Experimental & Molecular Medicine, scientists from the USC Stem Cell laboratory of Rong Lu share new discoveries about the influence of multipotent progenitor cells (MPPs) that are co-transplanted along with stem cells during bone marrow transplants.

“This is the first study to investigate the influence of MPPs, which we found stimulated stem cells to produce more T cells,” said Lu, the study’s corresponding author and an associate professor of stem cell biology, biomedical engineering, medicine, and gerontology at USC. “Improving T cell production in bone marrow transplantation can help prevent infections, a major complication that can be fatal for patients undergoing this treatment.”

In the study, first author Zheng Wang and his colleagues used genetic labels to “barcode” individual stem cells in bone marrow transplants in mice. The bone marrow transplants included MPPs along with blood-forming or “hematopoietic” stem cells (HSCs)–similar to what patients receive when being given bone marrow transplants to treat leukemia or other life-threatening conditions.

The scientists then tracked the blood production of the barcoded HSCs over a short-term period of 2.5 months and a long-term period of 6.5 months. When co-transplanted with MPPs, the HSCs produced many different cell types in the short-term, but ultimately increased their production of T cells in the long-term.

“The more we learn about these cellular interactions, the more we can inform clinicians about how to optimize bone marrow transplants for patients,” said Lu.

Additional co-authors include Du Jiang, Mary Vergel-Rodriguez, and Anna Nogalska from the Lu Lab.

The research was funded by the Chongqing Natural Science Foundation (cstc2019jcyj-msxmX0421), National Institutes of Health (R00-HL113104, R01HL135292, R01HL138225, and R35HL150826). Rong Lu is a scholar of the Leukemia & Lymphoma Society (LLS-1370-20) and was a Richard N. Merkin Assistant Professor.

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Graphic novel puts prescription opioid addiction in the spotlight

Published January 17, 2023

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New Graphic Novel Heightens Awareness of Prescription Opioid Addiction

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New Graphic Novel Heightens Awareness of Prescription Opioid Addiction
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“Jackie’s Pain,” the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences’ latest health literacy publication, explains the risks of prescription opioid addiction.

The comic-book-style graphic novel is the 11th publication in the popular health literacy series created by longtime faculty member Mel Baron, PharmD ’57, and producer Gregory B. Molina, combining health information with dramatic storytelling and illustrations. Published in both Spanish and English, the booklet was designed to be distributed in the community at safety-net clinics, health fairs, pharmacies and other locations.

It tells the story of Jackie, whose adult son Luis becomes addicted to opioids after finding old prescription painkillers that Jackie had not discarded after recovering from knee surgery.

Jackie begins going to a support group for parents of addicted children as well as meditating to manage stress. She learns how to use naloxone in case her son has another overdose, and encourages him to try a support group.

Written and directed by Gabriela Lopez de Dennis, illustrated by Los Angeles graphic design firm TinyTeam LLC and designed by Soap Studio Inc., the graphic novel covers fentanyl, sharing opioids prescribed by a doctor, and how to safely dispose of unused or expired opioids. It also addresses what naloxone is and how to use it, getting help for opioid use disorder, and safer ways to get relief from pain.

Timely information about drug-related dangers

The graphic novel comes at a time when the number of drug overdose deaths has quintupled since 1999, and increased by nearly 30% from 2019 to 2020, according to the Centers for Disease Control and Prevention. Nearly 75% of the 91,799 drug overdose deaths in 2020 involved an opioid.

“We hear a lot of questions from parents about what to look for as far as opioid addiction and the booklets are extremely well made,” says Elaine Di Simone, outpatient/substance use disorder program director at Clinica Romero, a federally qualified health center where trained community leaders called promotoras are distributing the publication to local, at-risk populations. “These are very helpful for our parents of our youth program.”

Numerous experts on pain management and addiction, preventive medicine and health literacy–including Baron, Jennifer B. Unger, PhD, Siddarth Puri, MD, Aurora Geysimonyan, MPH, Edward Padilla, Melissa Durham, PharmD and Gene Lang, PharmD–served as script consultants.

“Especially today with so much misinformation, we want the appropriate information to reach the public,” Baron says. “Packing expert advice in an entertaining format helps ensure the public health message gets through. Our graphic novels fulfill a vital need by reaching underserved communities and educating patients about drug-related dangers. It’s part of what pharmacy is all about.”

The project was supported by the USC Mann School, UniHealth Foundation, USC Good Neighbors Campaign, L.A. CARE Health Plan, Keck Medicine of USC, and Beit T’Shuvah, a residential addiction recovery center whose leadership, staff and clients provided insights and contributions to the development of the publication.

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How to rewind the clock on arthritic cartilage

Published January 14, 2023

8097 https://stemcell.keck.usc.edu/rewind-clock-on-arthritic-cartilage/
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How to rewind the clock on arthritic cartilage … stat!
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A new study in Aging Cell describes how a key protein, called Signal Transducer and Activator of Transcription 3 (STAT3), might turn back the clock on aging cartilage that leads to osteoarthritis.

“STAT3 performs an astonishing repertoire of roles in development and regeneration, as well as inflammatory disease and cancer. In this study, we found an innovative chemical approach for reversing aging of joint-forming cells in a clinically relevant manner, because this intervention is simple and fully controlled,” said the study’s co-corresponding author Denis Evseenko, who is an Professor of Orthopaedic Surgery, and Stem Cell Biology and Regenerative Medicine at USC, and holds the J. Harold and Edna LaBriola Chair in Genetic Orthopedic Research.

“We wanted to understand the role of STAT3 in cartilage cells during embryonic development as well as in the context of osteoarthritis,” said co-corresponding author Steve Horvath, a Professor of Human Genetics and Biostatstics at UCLA.

To accomplish this, first authors Arijita Sarkar, Nancy Q. Liu and their colleagues at USC and UCLA performed a series of experiments to uncover how STAT3 turns genes on and off through a process known as epigenetic regulation. Specifically, the team identified patterns of epigenetic regulation that correlate with the age of cartilage cells. These correlations served as the basis for creating what the researchers dubbed an “epigenetic clock” for cartilage cells.

By using a molecule to activate STAT3, they were able to reverse the hands of the epigenetic clock–turning on many genes and creating an epigenetic pattern typical of younger cartilage cells. When they genetically inactivated STAT3, the epigenetic clock ticked faster–turning off many genes and promoting an epigenetic pattern observed in older cartilage cells.

The scientists then focused their attention on an important enzyme called DNA methyltransferase 3 beta (DNMT3B), which interacts with STAT3. When STAT3 was inactivated, DNMT3B kicked into high gear to add aging marks to the DNA molecule, and promoted the progression of knee osteoarthritis in injured mice.

In the arthritic knee cartilage of the mice, there was a significant population of cartilage cells that appeared to be turning back time and reverting to an immature state.

“These cells may be assuming more embryonic-like state as an attempt to enhance their capacity to develop new knee cartilage,” said Sarkar, who is a postdoc in the Evseenko Lab.

Unfortunately, while these immature cells make cartilage that is youthfully regenerative during embryonic development or acute injury, they seemed to create cartilage that is dysfunctionally immature in the context of a chronic condition such as osteoarthritis.

“When present on a longer term basis, hyperactivation of the immature program in cartilage cells is likely to promote inflammation and, ultimately, degeneration and fibrosis,” said Liu, a senior scientist in the Evseenko Lab.

In the future, the results of this study can inform the quest to develop treatments that harness STAT3’s power to promote regeneration without tapping into its tendency to trigger inflammation.

Additional co-authors include Jenny Magallanes, Jade Tassey, Siyoung Lee, Ruzanna Shkhyan, Youngjoo Lee, Jinxiu Lu, Yuxin Ouyang, Hanhan Tang, Fangzhou Bian, Litao Tao, and Neil Segil from USC, and Jason Ernst and Karen M. Lyons from UCLA.

This work was supported by grants from the National Institutes of Health (R01AR071734 and R01AG058624), Department of Defense (W81XWH-13-1-0465), and the California Institute for Regenerative Medicine (TRAN1- 09288).

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How USC-led innovation can solve global challenges

Published January 12, 2023

With nearly $1 billion in actively funded research, USC is among the nation’s leading institutions for innovative, impactful discovery. Leading that effort is Ishwar Puri, who arrived at USC in 2021 and was recently promoted to senior vice president for research and innovation.

In the two years since his arrival, the university has continued to build on its research successes, winning major federal grants for research and innovation in computing, biomedical device and drug therapy development, medical research, as well as collaborative research projects with local governments and organizations that solve social problems and policy issues.

Puri has been charged with increasing interdisciplinary partnerships and speeding up discovery in an era of increasingly tech-dependent, rapid scientific inquiry. We spoke with the internationally recognized scientist and engineer about some of the past year’s major accomplishments, what might be in store for 2023 and how USC-led innovation can solve global challenges.

Congratulations on your new title. The most notable change is the addition of innovation under the umbrella of research. What does that new area of focus represent, practically?

Thank you, but really the story isn’t about me — it’s about USC President Carol L. Folt’s vision for the university since she arrived. During her time at USC, our sponsored research has increased at 7% annually, which would put us close to doubling that figure by 2028 or so. Money isn’t everything; it is trumped by impact. So, Dr. Folt has asked us to work toward audacious moonshots in areas such as computing and health. She has tasked us with improving our impact on society by developing innovative solutions for complex problems.

Money isn’t everything; it is trumped by impact.

Ishwar Puri

Innovation can take many forms. It can be through entrepreneurship, licensing to corporate entities and also thinking in a different way. If you think of sustainability, it’s not just about climate change research or providing solutions for electrification or other forms of renewable energy. Sustainability is about finding the kind of human solutions that will take us away from fossil fuel consumption. It’s finding environmentally friendly ways to eliminate or reduce waste. These are human problems, social science problems, health problems. That is where innovation comes in.

Practically, we are developing a partnership model of innovation and entrepreneurship. We are working with all our schools to help each of them flourish. We help them take their best examples and accelerate these through central means, including the Alfred E. Mann Institute, which is now part of the Office of Research and Innovation.

You mentioned an emphasis on research and innovation that is impactful. What are some examples of USC research that made an impact in 2022?

Due to the depth and breadth of expertise at USC, researchers across the university conduct impactful research every day. One example is our world-leading work in Alzheimer’s disease research. Publications (such as a recent one from Paul Thompson, Arthur Toga and Julie Zissimopoulos) have greatly expanded our collective knowledge of the causes and potential solutions for neurodegenerative cognitive diseases. In other areas, Kristina Lerman and Emilio Ferrara from the USC Information Sciences Institute examined the effects of polarization on social media users. Gale Sinatra co-authored a piece for The Conversation that examined how Hollywood perpetuates myths that fuel science skepticism. And earlier this year, Sergey Nuzhdin partnered with AltaSea at the Port of Los Angeles to open a massive 6,000-square-foot seaweed lab that will help grow the blue economy. These are just a few examples; there are countless others.

How is USC looking to expand its impact in 2023?

The president’s view is that if we’re really going to have an impact, it must be through partnerships. USC has very strong local community partnerships in environmental health, for instance. We’ve also started to form partnerships with area universities, notably with UCLA and Caltech, on grant proposals that combine the strengths of each institution to address complex challenges. In fact, USC is the lead partner of the new National Science Foundation Innovation Corps Hub: West Region, a consortium of engineers and scientists from top research universities in the Western United States. And because we are committed to developing a diverse talent pipeline, we are partnering with minority-serving institutions and community colleges through outreach activities and other partnerships. The president has insisted on and successfully developed a culture of collaboration among university leaders.

That emphasis on collaboration applies within the university as well?

Yes. Take entrepreneurship for example. When you think of entrepreneurship in the university setting, you typically think of the classic tech transfer model: Do some research, and then commercialize it. But the real talent at USC lies in the sheer number of our potential entrepreneurs. We have business-minded undergraduate and graduate students, postdocs and faculty members, and to support them we must meld research with experiential learning, where different parts of the university come together.

We do amazing discovery research. But maybe it’s not just the researcher who takes that work to fruition as a solution. Instead, it is a partnership with students, postdocs and others.

Ishwar Puri

We do amazing discovery research. But maybe it’s not just the researcher who takes that work to fruition as a solution. Instead, it is a partnership with students, postdocs and others. In partnership with the provost and the senior vice president for health sciences, the Office of Research and Innovation now works with deans to develop programs that take advantage of internal partnerships in different areas of the university. We cannot afford to segment or sector different areas because they are synergistic. The future lies in partnership and collaboration.

Speaking of the future, if you were a young researcher, why would you want to be at USC?

It really comes down to three things: excellence, scale and opportunity. Undoubtedly, USC offers excellence and hence we are a great attractor of talent. USC also offers scale. Where else in the world can one go to collaborate with leading scholars in communications, technology and cinematic arts? Not many other places. That school of schools model, and the scales of those schools, coupled with our excellence in health sciences, technology, humanities and the arts is a great launch pad for a young person’s career. In addition, the president’s expansive research vision for the university — increased partnerships; investments in internal support programs like internal grants, startups and mentoring; and her moonshots — provides young researchers with incredible opportunities to rub shoulders with experienced academics who have been in the business for a while and contributes to everyone’s success.

These all combine to make USC a very exciting place to work. I feel very fortunate to have the opportunity to be at USC and work with brilliant researchers across disciplines. This truly is an exceptional place with unrivaled talent and leadership.

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How old is your brain, really? Artificial intelligence knows

Published January 11, 2023

The human brain holds many clues about a person’s long-term health — in fact, research shows that a person’s brain age is a more useful and accurate predictor of health risks and future disease than their birthdate. A new artificial intelligence model that analyzes MRI brain scans developed by USC researchers could be used to accurately capture cognitive decline linked to neurodegenerative diseases like Alzheimer’s much earlier than previous methods.

Brain aging is considered a reliable biomarker for neurodegenerative disease risk. Such risk increases when a person’s brain exhibits features that appear “older” than expected for someone of that person’s age. By tapping into the deep learning capability of the team’s novel AI model to analyze the scans, the researchers can detect subtle brain anatomy markers that are otherwise very difficult to detect and that correlate with cognitive decline. Their findings, recently published in the journal Proceedings of the National Academy of Sciences, offer an unprecedented glimpse into human cognition.

“Our study harnesses the power of deep learning to identify areas of the brain that are aging in ways that reflect a cognitive decline that may lead to Alzheimer’s,” said Andrei Irimia, assistant professor of gerontology, biomedical engineering and neuroscience at the USC Leonard Davis School of Gerontology and corresponding author of the study.

People age at different rates, and so do tissue types in the body. We know this colloquially when we say, ‘So-and-so is 40, but looks 30.’

Andrei Irimia, USC Leonard Davis
School of Gerontology

“People age at different rates, and so do tissue types in the body,” Irimia said. “We know this colloquially when we say, ‘So-and-so is 40, but looks 30.’ The same idea applies to the brain. The brain of a 40-year-old may look as ‘young’ as the brain of a 30-year-old, or as ‘old’ as that of a 60-year-old.”

Brain aging: A more accurate alternative to existing methods

Researchers collated the brain MRIs of 4,681 cognitively normal participants, some of whom went on to develop cognitive decline or Alzheimer’s disease later in life.

Using these data, they created an AI model called a neural network to predict participants’ ages from their brain MRIs. First, the researchers trained the network to produce detailed anatomic brain maps that reveal subject-specific patterns of aging. They then compared the perceived (biological) brain ages with the actual (chronological) ages of study participants. The greater the difference between the two, the worse the participants’ cognitive scores, which reflect Alzheimer’s risk.

The results show that the team’s model can predict the true (chronological) ages of cognitively normal participants with an average absolute error of 2.3 years, which is about one year more accurate than an existing, award-winning model for brain age estimation that used a different neural network architecture.

“Interpretable AI can become a powerful tool for assessing the risk for Alzheimer’s and other neurocognitive diseases,” said Irimia, who also holds faculty positions with the USC Viterbi School of Engineering and the USC Dornsife College of Letters, Arts and Sciences.

“The earlier we can identify people at high risk for Alzheimer’s disease, the earlier clinicians can intervene with treatment options, monitoring and disease management.“

Brain aging: differences according to sex

The new model also reveals sex-specific differences in how aging varies across brain regions. Certain parts of the brain age faster in males than in females, and vice versa.

Males, who are at higher risk of motor impairment due to Parkinson’s disease, experience faster aging in the brain’s motor cortex, an area responsible for motor function. Findings also show that, among females, typical aging may be relatively slower in the right hemisphere of the brain.

An emerging field of study shows promise for personalized medicine

Applications of this work extend far beyond disease risk assessment. Irimia envisions a world in which the novel deep learning methods developed as part of the study are used to help people understand how fast they are aging in general.

“One of the most important applications of our work is its potential to pave the way for tailored interventions that address the unique aging patterns of every individual,” Irimia said.

“Many people would be interested in knowing their true rate of aging. The information could give us hints about different lifestyle changes or interventions that a person could adopt to improve their overall health and well-being. Our methods could be used to design patient-centered treatment plans and personalized maps of brain aging that may be of interest to people with different health needs and goals.”

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Consumption of fast food linked to liver disease

Published January 11, 2023

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https://news.keckmedicine.org/consumption-of-fast-food-linked-to-liver-disease/
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Consumption of fast food linked to liver disease

Risk of liver damage is highest for those with obesity or diabetes
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LOS ANGELES — The new year has begun, and with it, resolutions for change.
A study from Keck Medicine of USC published today in Clinical Gastroenterology and Hepatology gives people extra motivation to reduce fast-food consumption.
The study found that eating fast food is associated with nonalcoholic fatty liver disease, a potentially life-threatening condition in which fat builds up in the liver.
Researchers discovered that people with obesity or diabetes who consume 20% or more of their daily calories from fast food have severely elevated levels of fat in their liver compared to those who consume less or no fast food. And the general population has moderate increases of liver fat when one-fifth or more of their diet is fast food.
“Healthy livers contain a small amount of fat, usually less than 5%, and even a moderate increase in fat can lead to nonalcoholic fatty liver disease,” said Ani Kardashian, MD, a hepatologist with Keck Medicine and lead author of the study. “The severe rise in liver fat in those with obesity or diabetes is especially striking, and probably due to the fact that these conditions cause a greater susceptibility for fat to build up in the liver.”
While previous research has shown a link between fast food and obesity and diabetes, this is one of the first studies to demonstrate the negative impact of fast food on liver health, according to Kardashian.
The findings also reveal that a relatively modest amount of fast food, which is high in carbohydrates and fat, can hurt the liver. “If people eat one meal a day at a fast-food restaurant, they may think they aren’t doing harm,” said Kardashian. “However, if that one meal equals at least one-fifth of their daily calories, they are putting their livers at risk.”
Nonalcoholic fatty liver disease, also known as liver steatosis, can lead to cirrhosis, or scarring of the liver, which can cause liver cancer or failure. Liver steatosis affects over 30% of the U.S. population.
Kardashian and colleagues analyzed the most recent data from the nation’s largest annual nutritional survey, the 2017-2018 National Health and Nutrition Examination Survey, to determine the impact of fast-food consumption on liver steatosis.
The study characterized fast food as meals, including pizza, from either a drive-through restaurant or one without wait staff.
The researchers evaluated the fatty liver measurement of approximately 4,000 adults whose fatty liver measurements were included in the survey and compared these measurements to their fast-food consumption.
Of those surveyed, 52% consumed some fast food. Of these, 29% consumed one-fifth or more daily calories from fast food. Only this 29% of survey subjects experienced a rise in liver fat levels.
The association between liver steatosis and a 20% diet of fast food held steady for both the general population and those with obesity or diabetes even after data was adjusted for multiple other factors such as age, sex, race, ethnicity, alcohol use and physical activity.
“Our findings are particularly alarming as fast-food consumption has gone up in the last 50 years, regardless of socioeconomic status,” said Kardashian. “We’ve also seen a substantial surge in fast-food dining during the COVID-19 pandemic, which is probably related to the decline in full-service restaurant dining and rising rates of food insecurity. We worry that the number of those with fatty livers has gone up even more since the time of the survey.”
She hopes the study will encourage health care providers to offer patients more nutrition education, especially to those with obesity or diabetes who are at higher risk of developing a fatty liver from fast food. Currently, the only way to treat liver steatosis is through an improved diet.
Jennifer Dodge, MPH, assistant professor of research medicine and population and public health sciences at the Keck School of Medicine of USC and Norah Terrault, MD, MPH, a Keck Medicine gastroenterologist and division chief of gastroenterology and liver diseases at the Keck School, were also authors on the study.

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Study shows how liver cancer hijacks circadian clock machinery inside cells

Published January 10, 2023

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https://keck.usc.edu/study-shows-how-liver-cancer-hijacks-circadian-clock-machinery-inside-cells/
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Study shows how liver cancer hijacks circadian clock machinery inside cells

Researchers from the Keck School of Medicine of USC are now one step closer to understanding how to halt the spread of the deadly disease in the body.
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The most common type of liver cancer, hepatocellular carcinoma (HCC), is already the third leading cause of cancer-related deaths globally–and cases are on the rise, both in the U.S. and worldwide. While chemotherapy, surgery and liver transplants can help some patients, targeted treatments for HCC could save millions more lives.

Recent studies have offered clues about one potential target: the circadian clock proteins inside cells, which help coordinate changes in the body’s functioning over the course of a day. But most of this research only hints at an indirect link between circadian clock function and HCC, for instance the observation that cells collected from patients with liver cancer have disrupted circadian rhythms.

Now, a study led by researchers at the Keck School of Medicine of USC not only directly links circadian clock proteins to liver cancer, but also shows precisely how cancer cells hijack circadian clock machinery to divide and spread. The research, just published in the journal Proceedings of the National Academy of Sciences, also found that inhibiting key clock proteins can prevent cancer cells from multiplying.

“Earlier studies didn’t give us a real handle on how we could use a specific treatment to target processes within liver cancer cells. In this paper, we’re making the first steps toward that,” said the study’s senior author, Steve A. Kay, PhD, University and Provost Professor of Neurology, Biomedical Engineering and Quantitative Computational Biology at the Keck School of Medicine of USC and director of the USC Michelson Center for Convergent Bioscience.

The research is a collaboration between cell biology experts and clinicians at the USC Norris Comprehensive Cancer Center, which is known for its leadership in clinical trials for various cancers, including HCC.

“We are very excited to find a new, innovative treatment strategy that may ultimately improve outcomes for patients with liver cancer,” said Heinz-Josef Lenz, MD, a professor of medicine and preventive medicine, associate director for clinical research and co-leader of the Gastrointestinal Cancers Program at USC Norris. “By targeting the circadian clock, we are not only targeting tumor cells but also the area around the tumor, which can help increase the efficacy of other targeted treatments.”

Interrupting the cell cycle

To elucidate the role of circadian clock proteins in HCC, Kay, Lenz and their colleagues conducted a series of experiments, using a combination of cell culture, genomic analysis and animal models.

First, the researchers showed that two key clock proteins, known as CLOCK and BMAL1, are critical for the replication of liver cancer cells in cell culture. When CLOCK and BMAL1 are suppressed, cancer cells’ replication process was interrupted–ultimately causing cell death, or apoptosis. Triggering apoptosis, during which a cell stops dividing, then self-destructs, is the goal of many modern cancer treatments.

Next, the team drew on their tool chest of genomic samples, built through years of research on circadian clock proteins in the body, to further understand the role of CLOCK and BMAL1. Among other findings, they showed that eliminating the clock proteins reduced levels of the enzyme Wee1 and increased levels of the enzyme inhibitor P21.

“That’s exactly what you want, because when it comes to cancer cell proliferation, P21 is a brake and Wee1 is a gas pedal,” said Kay, who also co-directs the USC Norris Center for Cancer Drug Development.

Finally, the researchers tested their findings in vivo. Mice injected with unmodified human liver cancer cells grew large tumors, but those injected with cells modified to suppress CLOCK and BMAL1 showed little to no tumor growth.

Developing targeted therapies

Understanding how cancer cells hijack circadian clock proteins is a big step toward halting the spread of liver cancer, but the researchers have more questions to answer. For example, Kay and his team hope to explore the relationship between circadian clock proteins, Wee1, and the P53 gene. The gene helps prevent the growth of tumors in the body, and mutations in P53 have long been linked with a heightened risk for various cancers.

“We really need to understand that relationship to better identify which patients might benefit most from a targeted therapy against CLOCK and BMAL1,” Kay said.

He and his team also hope to begin testing experimental drugs that can target CLOCK and BMAL1 in patients with liver cancer. The work is part of their larger body of research that analyzes circadian clock proteins in several types of cancer, including glioblastoma, leukemia and colorectal cancer.

About this study

In addition to Kay and Lenz, the study’s other authors are Meng Qu and Alexander Vu from the Department of Neurology, Keck School of Medicine of USC; Raymond Wu and Hidekazu Tsukamoto from the Department of Pathology, Keck School of Medicine of USC; Guoxin Zhang and Jeremy N. Rich from the Department of Neurology, University of Pittsburgh; Han Qu and Zhenyu Jia from the Department of Botany and Plant Sciences, University of California, Riverside; and Wendong Huang from the Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center.

This work was supported by the University of Southern California Norris Comprehensive Cancer Center Translational Team Accelerator Program; the National Institutes of Health [P30 CA047904, CA238662, CA197718, NS103434, CA139158, DK124627, P50 AA011999, U01 AA027681]; the United States Department of Agriculture National Institute of Food and Agriculture Grant [2019-67022-29930]; the Department of Veterans Affairs [5 I01BX001991]; and a Biomedical Laboratory Research and Development Research Career Scientist Award [5 IK6BX004205].

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