“We combined a multifunctional nano drug that suppresses a cancer gene with an immune checkpoint inhibitor, which helps the immune system recognize and attack cancer cells,” said Vladimir Ljubimov, MD, assistant professor of Neurosurgery at Cedars-Sinai and first author of the multicenter study. “The tiny, nano-sized polymers enabled the treatment to cross the blood-brain barrier that blocks many anticancer drugs from reaching the brain.” 

Other Cedars-Sinai authors include: Tao Sun, Paul Z. Wang, Alexander V. Ljubimov and Keith L. Black.

Other authors include: Jiawei Wang, Lian Li, Eggehard Holler, Jindrich Kopeček, Julia Y. Ljubimova and Jiyuan Yang.

Funding: Research was supported in part by NIH/NCI R01 Grants CA188743, CA206220, CA230858 (JYL), CA209921 (EH), CA284247 (AL), CA246716 (JK) and NIH/NIGMS GM95606 (JK), and the University of Utah Research Foundation (JK, JY). The authors thank Dr. Anna Galstyan and Dr. Oliver Braubach for their professional contribution during data development.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

The study, published in the peer-reviewed journal Digestive Diseases and Sciences, provides key validation of the breath test. 

Gastrointestinal diseases affect tens of millions of Americans and nearly 1 billion people worldwide. Pinpointing the source of the gut gases in same-day testing of patients could have applications to a wide range of digestive diseases, according to study investigators. Methane is associated with constipation and hydrogen sulfide with less constipation.

“Identifying the relevant microorganisms, their precise gut locations and their relationship to symptoms is critical,” said Mark Pimentel, MD, executive director of the Medically Associated Science and Technology (MAST) Program at Cedars-Sinai and corresponding author of the study. “This information opens up important opportunities to develop new therapies for bloating, diarrhea and constipation.”

Other Cedars-Sinai authors include: Maria Jesus Villanueva-Millan, PhD, Gabriela Leite, PhD, Ruchi Mathur, MD, Ali Rezaie, MD, MSc, Cristina Moreno Fajardo, MS, Juliana de Freitas Germano, PhD, Walter Morales, BS, Maritza Sanchez, BS, Ignacio Rivera, Gonzalo Parodi, BS, Stacy Weitsman, MS, Mohamad Rashid, MBChB, Ava Hosseini, MPH, Daniel Brimberry, PhD, and Gillian M. Barlow, PhD.

Acknowledgments: The authors thank the REIMAGINE Study Group for their assistance in obtaining samples. The REIMAGINE Study Group includes: Christopher Almario MD, Benjamin Basseri MD, Yin Chan MD, Bianca Chang MD, Derek Cheng MD, Pedram Enayati MD, Srinivas Gaddam MD, Laith Jamil MD, Quin Liu MD, Simon Lo MD, Marc Makhani MD, Deena Midani MD, Mazen Noureddin MD, Kenneth Park MD, Shirley Paski MD, Nipaporn Pichetshote MD, Shervin Rabizadeh MD, Soraya Ross MD, Omid Shaye MD, Rabindra Watson MD, Ali Rezaie MD, and Mark Pimentel MD.

Funding: This study was funded in part by funds from the Scott Gray Foundation, Justine Stamen Arrillaga & John Arrillaga, Arrillaga Foundation, the Steve Perry Foundation, the Eli Gottesdiener Foundation, the Nima Taghavi Foundation, the DiCecco Family Foundation, and the National Philanthropic Trust.

Competing interests: M.P. is a consultant for Ferring Pharmaceuticals Inc., Salvo Health, Dieta Health, Cylinder Health Inc., and Vivante Health Inc. M.P. has received grant support from Bausch Health and Synthetic Biologics. R.M. has received grant support from Bausch Health. A.R. is a consultant/speaker for and has received grant support from Bausch Health. Cedars-Sinai has a licensing agreement with Gemelli Biotech and Hobbs Medical. A.R., M.P., and R.M. have equity in Gemelli Biotech and Good LFE. M. P. has equity in Cylinder Health and Salvo Health. The remaining authors report no conflicts of interest.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Her outlook changed after Marootian participated in the Cedars-Sinai’s recent Prompt-A-Thon event. 

After six hours of hands-on experience building an AI-driven product—with coaching from Cedars-Sinai experts—Marootian said she feels more prepared to use AI tools to improve workflows and solve problems.

And during the Prompt-A-Thon, Marootian’s human resources team developed a tool that helps write job descriptions while following Cedars-Sinai’s tone, style and compliance needs.

“My hope in the Prompt-A-Thon was to raise my comfort level with artificial intelligence and eventually incorporate it in areas that would help our leaders with key business processes,” Marootian said. “I really appreciated that we leveraged artificial intelligence in a way that fostered creativity in addressing issues and challenges we are navigating as an organization.”  

The Prompt-A-Thon included representatives from every corner of the health system, from clinical informatics and digital strategy to emergency medicine, and performance improvement.

At the event, participants worked alongside technical coaches and created their own custom AI prototypes, then optimized the solutions through several iterations of improvements and developed roadmaps for expanding the tools for broader uses. They then developed “pitches” to showcase what they developed to a panel of judges.

“Our big bet for AI is on our people,” said Mouneer Odeh, MA, inaugural chief data and artificial intelligence officer, who led the event. “We are eager to train our colleagues so they can use AI technology to solve their own problems, because they understand those challenges better than anyone and are most motivated to use AI to make their work experience better and more productive.”

Each team presented its solution to a panel of judges that evaluated each team on their demonstrated understanding of artificial intelligence, a thoroughness-of-prototype evaluation, potential impact of protype and overall clarity of presentation. 

The winning team came from performance improvement with the development of a prototype called Pathways for Results, Improvement, Mastery, and Excellence (PRIME). The prototype aims to speed up curating educational materials for different audiences and learning objectives.

Although Marootian wasn’t part of the winning team, she said the event was a win for all.

“I see Cedars-Sinai rapidly moving to open the door to innovation, which will positively impact our workforce and our patients,” Marootian said. “One of the reasons I love working here is the consistent focus on innovation and creative thinking in addressing issues. The Prompt-A-Thon was a true representation of how we show up as an organization.”

Read more on the Cedars-Sinai Newsroom: Cedars-Sinai Announces Informatics Leadership Appointments

“The key to good outcomes with enoxaparin is careful selection of candidates,” said Lee D. Lam, PharmD, who monitors heart pump patients in the Mechanical Circulatory Support Program at the Cedars-Sinai Comprehensive Transplant Center. “For instance, patients must have a certain level of kidney functioning and lack a history of bleeding, blood clots or allergic reactions to drugs. Due to potential bleeding risks, enoxaparin should not be used within 30 days after the initial surgery to implant the heart pump.”

Lam is the first author of the new study. Oksana Volod, MD, professor of Pathology and Laboratory Medicine at Cedars-Sinai, is the corresponding author.

For the study, investigators analyzed medical records from 85 heart failure patients who had been implanted with left ventricular assist devices (LVADs) to boost the heart’s performance. They found that enoxaparin, which a patient can inject at home, is a treatment strategy that can be achieved at a small fraction of the cost of treatment in a hospital setting while improving quality of life. Use of this drug also was correlated with longer patient survival over a three-year period without major bleeding or blood clot events when compared with in-hospital bridging.

Other Cedars-Sinai authors include Lawrence S. Czer, Carmelita Runyan, Ieeshiah Otarola, Jason Jang, Jason Lau, Mignon Gau, Katrina Hernandez, Tram Ngo, Mario Aguillon, Newman Huie, Julie W. Chen, Robert Cole and Jaime Moriguchi.

Follow Cedars-Sinai Academic Medicine on LinkedIn for more on the latest basic science and clinical research from Cedars-Sinai.

The plan, published in the peer-reviewed journal Neurology® Clinical Practice, covers all aspects of the complicated medication regimen, from guidelines for emergency management of patients on lecanemab, and biweekly patient assessments, to a comprehensive informed consent process, including a provision for an authorized surrogate for adult patients who may lack the cognitive ability to manage their own care.

Lecanemab, recently approved by the Food and Drug Administration (FDA), is a complex therapy requiring biweekly infusions, periodic imaging and laboratory tests, clinical patient assessment, and drug interaction screening. Rita Shane, PharmD, vice president and chief pharmacy officer at Cedars-Sinai, said the guidelines will help guide the management of future complex therapies.

“With an increasing number of FDA approvals of these types of high-cost, innovative therapies, a comprehensive, multidisciplinary planning process not only supports access, but also safety for patients,” Shane said. “The process design we implemented for lecanemab can serve as a blueprint to support safe and effective management of these new, complex neurologic therapies at institutions across the country.”

Additional authors: Sarah Kremen, MD; Zaldy S. Tan, MD, MPH; Hai Tran, PharmD; Thanh G. Tu, PharmD; Nancy L. Sicotte, MD.

Funding: The authors report no targeted funding.

Conflict of interest: S. Kremen was a consultant for Eli Lilly and Company relating to donanemab.

Follow Cedars-Sinai Academic Medicine on LinkedIn for more on the latest basic science and clinical research from Cedars-Sinai.

Atrial fibrillation is an irregular heart rhythm that can cause heart palpitations, shortness of breath, lightheadedness and other symptoms in some patients.

“Atrial fibrillation is a really common disease,” said Jessica Mao, MD, a cardiology fellow at the Smidt Heart Institute and first author of the study. “Our study aimed to understand why some patients have symptoms and others do not.”

Investigators specifically sought to better understand paroxysmal atrial fibrillation, a type of atrial fibrillation that lasts only a few hours or days. They aimed to correlate the magnitudes of skin sympathetic nerve activity with symptoms in patients with this type of arrhythmia.

Cedars-Sinai investigators followed symptoms in 35 patients with paroxysmal atrial fibrillation over seven days. The patients were fitted with a skin patch electrode on the chest that monitored skin sympathetic nerve activity. They were told to press a button on the device when they experienced symptoms that they usually would have during an atrial fibrillation episode. The most reported symptoms were palpitations, dizziness, shortness of breath and chest pain.

Among the enrolled patients, 16 had at least one episode of atrial fibrillation, and 24 had symptoms. The investigators noted that sympathetic nerve activity was elevated when people reported symptoms. They also noted that the symptoms may occur during normal rhythm or atrial fibrillation.

Studies show patients have fewer symptoms after they undergo catheter ablation, a procedure that destroys small areas of heart tissue and blocks abnormal electrical impulses. 

“The fact that many patients have fewer symptoms after this procedure while still having documented atrial fibrillation could indicate that the procedure modulates the nervous system,” Mao said.

Investigators plan additional studies with a larger patient population to strengthen their findings.

Other Cedars-Sinai investigators who worked on the study include Xiao Liu, MD, PhD; Anxhela Kote, BS; Taiga Andersson, MSHS; Xiaochun Li, PhD; Christine M. Albert, MD, MPH, FHRS; and Peng-Sheng Chen, MD, FHRS.

Funding: The study was partially funded by National Institutes of Health grants R01HL116690, R01HL139829, 1OT2OD028190, and T32HL116273, an American Heart Association grant 23IPA1052289, and the Burns & Allen Chair in Cardiology Research, Cedars-Sinai Medical Center.

Conflicts of Interest: Dr. Peng-Sheng Chen is a co-inventor of U.S. patent No: 10,448,852 awarded to Indiana University.

Visit Research News and follow Cedars-Sinai Academic Medicine on LinkedIn for more on the latest basic science and clinical research from Cedars-Sinai. 

Acute coronary syndrome refers to any condition that involves the blockage of blood flow to the heart, such as a heart attack.

The investigators previously reported the immune system of patients with acute coronary syndrome seems to be reactive to LL-37. Other studies have reported that LL-37 triggers an immune response that plays a role in autoimmune diseases such as psoriasis and systemic lupus. This led the investigators to hypothesize that LL-37 might contribute to an immune response that increases inflammation and leads to a tightening of blood vessels.

In this new study, published in JACC: Basic to Translational Science, the research team reports that LL-37 binds to antibodies, forming complexes that then bind to and activate platelets. These activated platelets form clots and can restrict blood flow.

“Platelets that normally should be quiescent become active in acute coronary syndrome, and they stay active even after a heart attack,” said Paul Dimayuga, PhD, research associate professor in the Department of Cardiology in the Smidt Heart Institute and first and corresponding author of the study. “Our data suggest the immune complex formed by antibodies against LL-37 adds to the platelet activation.”

To conduct the study, the investigators collaborated with the laboratory of Daniel Berman, MD, in the Smidt Heart Institute and the Department of Imaging. The laboratory is collecting blood plasma from study participants who undergo coronary artery CT imaging to evaluate their risk for a heart attack. They are following the patients over time to learn how the composition of their plasma changes.

The investigators studied the composition of the blood plasma of patients who went on to have a heart attack, as well as the blood plasma of patients who did not. Patients who suffered a heart attack had significantly higher levels of LL-37 antibodies before the heart attack than people who did not experience a heart attack. The investigators also found that people with acute coronary syndrome had increased levels of immune complexes that formed between these antibodies and LL-37.

Experiments demonstrated these complexes have the propensity to activate platelets, suggesting a novel immune-mediated pathway of platelet activation during a heart attack and potentially a target for therapy.

With additional research, the investigators hope to understand why some people have higher levels of LL-37 antibodies than others.

“The question is: Is there a biological process that drives certain people to have an immune response to LL-37, but not others?” Dimayuga said. “We would like to study the immune cells of these individuals to see if there is something peculiar about these cells.”

Other Cedars-Sinai investigators who worked on the study include Kuang-Yuh Chyu, MD, PhD; Xiaoning Zhao, PhD; Jianchang Zhou, PhD; Nicole Wai Man Lio, BS; Fernando Chernomordik, MD; Daniel Berman, MD; Prediman K. Shah, MD; and Bojan Cercek, MD, PhD.

Funding: The Heart Foundation, Eisner Foundation, Peterson Foundation, Corday Foundation, Spielberg Fund (Los Angeles, CA [PS]); The Eleanor and Harold Foonberg Endowed Chair in Cardiac Intensive Care Fund (Los Angeles, CA [BC]); Academic Affairs Department, Cedars-Sinai Medical Center (Los Angeles, CA), The Lydia Kitner Scholarship for Advanced Cardiovascular Training, the Milovicz grant for the Development of the Future Generation of Leaders in Medicine, and the Prof. Arieh Roth Scholarship from the Working Group in Acute Cardiac Care of the Israel Heart Society (Israel [FC]).

Read more in Cedars-Sinai Discoveries Magazine: A Better Model of Heart Disease Prediction

Inequities in pain medication treatment received postpartum, after giving birth, were found in a Cedars-Sinai study of 18,000 women. The disparities were observed even among patients reporting the highest pain levels.

The retrospective cohort study was published in The Joint Commission Journal on Quality and Patient Safety.

Both opioid and non-opioid pain medications given to patients were examined. Investigators wanted to see if the lower opioid doses reported in some studies finding racial and ethnic differences in peripartum pain management could be due to those patients receiving other kinds of drugs for their discomfort.

“Even after adjusting our analysis to include non-opioid medications, Black and Hispanic patients who reported the highest pain scores received lower doses of opioid-containing medication. The fact that they also received non-opioid drugs could not explain the lower opioid treatment they received when compared with white patients,” said Naomi Greene, PhD, principal investigator of the study and research assistant professor of  Obstetrics and Gynecology.

Pain associated with labor and delivery can make it challenging for women to care for themselves and their newborns. Investigators looked at many variables available in the electronic medical records of the patients who delivered at Cedars-Sinai over a three-year period, 2019−2021. White, Black, Asian and Hispanic women were part of the large cohort.

“We attempted to identify factors that might have mitigated the apparent differences, such as the number of pain assessments, use of epidurals, the amount of non-opioid medication, maternal age, the number of pregnancies, and body mass index. But none of these factors could account for the racial and ethnic disparities in the amount of effective opioid pain management given to them,” said Sarah J. Kilpatrick, MD, PhD, the Helping Hand of Los Angeles Chair in Obstetrics and Gynecology and senior author of the paper.

Investigators emphasize that further study is needed to identify what factors might explain the persistent racial and ethnic disparities in pain management that could point to potential interventions to eliminate the inequities.

“This study adds to the growing body of literature on peripartum pain medication disparity. While confirming previous findings, we added to it by showing that the amount of non-opioid medication used could not explain those disparities in opiate-based therapy given to patients in pain,” Greene said.

It is likely that pain perception and assessments are affected by a complex set of factors, the study authors noted.

“Healthcare provider beliefs, attitudes, and biases concerning pain rating in patients of different races and ethnicities are part of the challenge. Exploring this would necessitate a prospective intervention, such as a survey distributed to nurses and doctors to assess these beliefs and biases. Also, beyond recording a number for a pain score, we need to find ways to allow patients to directly assess their satisfaction with the pain management they are receiving,” Kilpatrick said.

Read more on the Cedars-Sinai Blog: Equitable, Personalized Care for Women and Children of Color

Ouyang, who is also a faculty member in the Division of Artificial Intelligence in the Department of Medicine, has authored several papers describing AI systems for analyzing datasets related to cardiovascular disease. He is the corresponding author of two new papers about the details of developing such systems.

One paper, a study published in JACC: Advances, investigates the selection of cases for an AI model to learn the impact on model performance. In this example, the models were trained to detect a cardiovascular condition called cardiac amyloidosis. This condition occurs when the body creates abnormal proteins that accumulate in the tissues of the heart, causing the heart to become stiff. This training was based on different definitions of the disease, and the study showed that this impacted the accuracy of the model.

“Because cardiac amyloidosis is underdiagnosed, an AI program trained on patients at high risk for the condition could help clinicians detect the condition,” Ouyang said.

Cedars-Sinai investigator Lily Stern, MD, also worked on the JACC: Advances study.

In another paper, a case study published in NEJM AI, Ouyang and colleagues used electrocardiogram (ECG) data to train deep-learning AI models to identify patients with heart failure, a condition in which the heart’s ability to pump blood is weakened. One program was asked to predict which patients corresponded with a diagnosis of heart failure in the patient record. The other was trained to predict the underlying measurement of disease severity. 

The investigators found that it was more informative for the model to be trained on the clinical measurement used to diagnose heart failure, called ejection fraction, rather than a heart failure diagnosis in the electronic health record.

“This paper shows you will get more precise outcomes if you train the AI model on more granular detailed data, such as numerical measurements, rather than a description or diagnosis, which are less reliable,” said Amey Vrudhula, a fellow at Cedars-Sinai and first author of the study.

“We've trained a lot of AI models in healthcare and have learned important lessons in their design that we hope other researchers can use for future work,” Ouyang said.

Cedars-Sinai investigator Neal Yuan, MD, also worked on the study.

Read more in Cedars-Sinai Discoveries: The Doctor Is Still the Boss in the AI Era

“We already knew that, at a specific wavelength and bandwidth, UVA is effective against some RNA viruses, like the common cold and coxsackievirus,” said Ali Rezaie, MD, medical director of the GI Motility Program, director of Bioinformatics at the MAST Program at Cedars-Sinai and corresponding author of the study. “Our study sought to understand whether UVA therapy was also effective against some strains and mutations of other RNA viruses, like SARS-CoV-2.”

Researchers studied three COVID-19 variants: Alpha, Beta and Delta. Live viruses were then extracted from patients and exposed to a single dose of UVA. Researchers examined the effects of UVA on each variant, both extracellularly—by directly exposing the virus to UVA while outside of a cell—and intracellularly—by exposing cells that had been infected with the virus to UVA. They found UVA produced benefits in both scenarios, regardless of the variant being studied.

When an infected cell was exposed to UVA, it was activated into an antiviral state, allowing it to fight back against the virus and suppress the pathway that allows the virus to replicate. Additionally, researchers found the dose level used in their study was tolerated well by cells, and there was no indication that the UVA light was causing harm to the cells themselves.

“More traditional modalities against RNA viruses, including antibodies and vaccines, are typically strain-dependent, meaning as the virus mutates, we are constantly chasing the mutations in order to find effective treatments,” said Gabriela Leite, PhD, lead author of the study and a lead project scientist for the MAST Program at Cedars-Sinai. “However, our research found evidence that UVA could potentially be an effective stand-alone or adjunct therapy regardless of the virus strain for future RNA epidemics.”

Rezaie and Leite said that the next steps are to develop more efficient UVA delivery systems inside the body in preparation of clinical trials.  

“History has taught us that viral epidemics are going to happen. We’re going to see future pandemics,” Rezaie said. “When we do, we need to be ready and have every effective tool available to combat these viruses.”

Other Cedars-Sinai investigators involved in the study include Sepideh Mehravar, Mark Pimentel, Ruchi Mathur, Gil Y. Melmed and Gillian M. Barlow. Additional authors include Volha Teagle.

Funding: This study was funded in part by Aytu biosciences and in part by the John and Geraldine Cusenza Family Foundation.

Read more from Cedars-Sinai Discoveries: What Did COVID-19 Teach Us for the Next Pandemic?

Pancreatic cancer is one of the most aggressive types of cancer, with an incidence rate that is steadily rising each year. While treatments have improved over the past decade, the five-year overall survival rate for the disease is still just 13%.

The research, led by Cristina Ferrone, MD, the Lippman Family Chair in Surgical Oncology and chair of the Cedars-Sinai Jim and Eleanor Randall Department of Surgery, sought to understand two elements of pancreatic cancers.

First, Ferrone and fellow investigators studied how human leukocyte antigen (HLA) class I complex—a system that presents targets to the immune system, thereby alerting the immune system that a cell is defective—is expressed to a varying degree in pancreatic cancers. If a patient has high levels of HLA class I expressed on the pancreatic cancer, it suggests that their body is better at fighting the cancer.

Next, investigators aimed to target a molecule called B7-H3, which is expressed on malignant cells to escape recognition and destruction by the immune system. In many patients, a high level of B7-H3 means that cancer cells can evade the body’s immune system.

The study, which was completed when Ferrone was a professor of Surgery at Harvard Medical School, found that B7-H3 was highly expressed in the majority of pancreatic cancers studied, and its immune-evading presence was associated with significantly worse patient survival.

Patients whose tumors had a low or negative B7-H3 expression but positive HLA class I expression—alerting the immune system of defective cells—had significantly improved survival.

However, patients with high B7-H3 expressions had consistently poor prognoses, regardless of their tumor’s HLA class I expression.

“Our research suggests that the positive impact provided by high HLA class I expression in pancreatic cancer may be overpowered by a high B7-H3 expression,” said Ferrone, corresponding author of the study. “These findings provide the rationale to leverage B7-H3 suppression as a target for immunotherapeutic approaches, such as CAR-T cells directed to B7-H3, as a strategy for pancreatic cancer patients to potentially improve survival.”

Ferrone said that, in recent years, physicians are trying to shift the therapeutic paradigm for the treatment of pancreatic cancer from a generalized chemotherapy approach to a more patient-specific precision medicine approach based on the individual characteristics of a patient’s tumor. She said that the results of this study indicate a rationale for the design of new Phase I/II clinical trials investigating the effectiveness of anti-B7-H3 monoclonal antibodies alone or in combination with standard of care chemotherapy regimens, as well as a CAR-T therapy aimed at B7-H3 for patients with pancreatic cancer.

“If trial results from this approach are positive,” Ferrone said, “targeting B7-H3 has the potential to significantly improve the efficacy of immunotherapies for pancreatic cancer patients and, eventually, overall survival rates for the disease.”

Additional authors include Giulia Cattaneo; Marco Ventin; Shahrzad Arya; Filippos Kontos; Theodoros Michelakos; Yurie Sekigami; Lei Cai; Vincenzo Villani; Francesco Sabbatino; Francine Chen; Ananthan Sadagopan; Vikram Deshpande; Paul A. Moore; David T. Ting; Nabeel Bardeesy; Xinhui Wang; Soldano Ferrone.

Funding: This work was supported by National Cancer Institute/National Institute of Health (NCI/NIH) grants [R03CA223886 and R03CA231766 to Cristina Ferrone and Soldano Ferrone; R01DE028172 and R01CA226981 to Xinhui Wang], Department of Defense Breakthrough Award Level 2 [W81XWH-16-1-0500 (BC190615) to Soldano Ferrone], Department of Defense Breakthrough Award Level 4 [W81XWH-20-1-0315 (BC190615) to Cristina Ferrone and Soldano Ferrone], Department of Defense Idea Award [W81XWH-20-PCRP-IDA (W81XWH2110433) to Xinhui Wang] grants, and Internal funding from the Department of Surgery at the Massachusetts General Hospital.

Read more from the Cedars-Sinai Blog: How to Manage Your Pancreatic Cancer Risk

Last month, four Cedars-Sinai residents competed in his honor for the 2024 Rubenstein Award for Excellence in Resident Research. The award series—created when Rubenstein worked at Cedars-Sinai—honors Rubenstein’s efforts to transform the medical center from a community hospital to a major academic hub.  

The award aims to foster clinical and translational research, enrich knowledge, and encourage the development of residents across Cedars-Sinai as investigators. 

“This competitive opportunity for young trainees showcases the work they have been doing to catapult clinical and translational research—which was the mission of Dr. Rubenstein’s work,” said Brennan Spiegel, MD, MSHS, chair of the Rubenstein Award Committee, professor of Medicine and director of Health Services Research at Cedars-Sinai. “These residents are an integral part of our research enterprise, ensuring the best-quality ideas and innovations are studied.”  

When he was a Cedars-Sinai resident in 2001, Spiegel competed for the Rubenstein Award. He took home first place.  

The top four finalists who presented their work on May 28, 2024, were residents Robert Kim, MD, PhD; Jeff Liang, MD; Joseph Lownik, MD, PhD; and Samuel Zhang, MD. Each went through a rigorous application process prior to stepping up to the podium. Each competitor submitted an original study abstract as well as a letter of support from their primary mentor.  

Lownik and Zhang took top honors, and each received a $3,000 cash prize.

Lownik’s research, titled “Machine Learning-Based Decision Support System for Clinical Flow Cytometry Analysis,” highlighted how investigators successfully implemented a pathologist-trained, artificial intelligence program to analyze clinical flow cytometry studies to help diagnose leukemia and lymphoma.

“As part of the physician-scientist training program in the Department of Pathology, research is a big part of my residency training, and Cedars-Sinai has been incredibly supportive of this project, and my mentor, Dr. Kitahara, has worked tirelessly on this project with me,” Lownik said. “This award is further validation of the importance of this work, as well as Cedars-Sinai’s commitment to improving patient care through the adaptation of artificial intelligence into the clinical workplace.”

Sumire Kitahara, MD, associate professor of Pathology and Laboratory Medicine at Cedars-Sinai, said, “Being Dr. Lownik’s mentor has been incredibly rewarding, especially given the opportune timing to embrace machine learning in clinical medicine. While I had limited experience with computational tools to analyze high-dimensional data, Dr. Lownik’s research background and interest in hematologic neoplasms and clinical flow cytometry, combined with his innovative use of machine learning algorithms, allowed us to transition these research tools into clinical practice. This is particularly significant in hematopathology, where advancements in flow cytometry are producing complex data.” 

The research focus of Zhang’s work is the “Feasibility of Left Anterior Descending Coronary Artery Sparing During Definitive Radiotherapy Planning for Locally Advanced Lung Cancer.” Zhang’s research is among the first to show that it is possible to drastically reduce radiation dose to critical parts of the heart—such as the coronary arteries, which supply the heart with blood and oxygen—without reducing the dose to a tumor or increasing the radiation to other normal organs nearby, such as the lungs. The work involves patients being treated with high-dose radiation and chemotherapy for advanced lung cancer.

“I’m so honored to receive this award from Cedars-Sinai, home to so many important advances in cardiology and oncology,” Zhang said. “I’m also proud to represent my Department of Radiation Oncology, which I feel is a true center of excellence and innovation within our field.”

Zhang’s mentor is Katelyn Atkins, MD, PhD, medical director and assistant professor of Radiation Oncology at Cedars-Sinai.  

“Dr. Zhang exemplifies the qualities of a successful resident physician and researcher, and it has been a joy to mentor him,” Atkins said. “Not only does he take phenomenal care of patients, but he also patiently teaches and mentors medical students and junior researchers and is a consummate team player.”

Atkins said Zhang also ambitiously chose research projects that required learning several new skill sets, to which he diligently committed.

“The work he presented for this award is part of a larger body of work in cardio-oncology that he has expertly put together and is pushing the leading edge of our field to help shape how we deliver safe and effective care.”

Kim’s original research, “Elucidating the Role of Sensory Cortical Areas in Short-Term Memory,” shows that human sensory cortical neurons and sensory model neurons can perform tasks requiring working memory, suggesting their involvement in complex cognitive functions—contrary to previous understanding—and highlighting potential therapeutic targets for neuropsychiatric and neurodegenerative conditions.

His mentors are Ueli Rutishauser, PhD, professor of Neurosurgery, Neurology and Biomedical Sciences and director of Human Neurophysiology Research and the Center for Neural Science and Medicine at Cedars-Sinai, and Chrystal Reed, MD, associate professor of Neurology and director of the Neurophysiology Fellowship Program.  

Liang’s presentation, “Development and Validation of Biomarker Index for Hepatocellular Carcinoma Treatment and Response,” focused on the development of a blood-based test that may be helpful for detecting and monitoring hepatocellular carcinoma, although additional tests are needed to confirm its accuracy. His mentor is Ju Dong Yang, MD, medical director of the Liver Cancer Program at Cedars-Sinai Cancer.  

Funding for this year’s event was provided by the Burns and Allen Research Institute and the Clinical and Translational Science Institute at Cedars-Sinai.  

Follow Cedars-Sinai Academic Medicine on X for more on the latest basic science and clinical research from Cedars-Sinai.

and led by a Cedars-Sinai investigator found that a medication used to treat COVID-19 also reduces a patient’s chances of developing delirium or coma, which is a form of delirium.

“This study continues our investigation of a protein called IL-6, which is produced by the body’s immune system in response to infection or injury,” said Shouri Lahiri, MD, director of the Neurosciences Critical Care Unit at Cedars-Sinai and senior author of the study. “We’ve previously shown that modulating IL-6 reduces delirium in a laboratory mouse model that we developed. This study shows that the effect also translates to human patients.”

Lahiri and co-investigators from Vanderbilt University Medical Center reviewed data on 253 patients hospitalized with COVID-19. Sixty-nine of those patients were treated with tocilizumab, a medication known to help with survival and recovery from COVID-19 but not previously studied in delirium.

“Across the world, millions of patients are suffering from delirium while critically ill, including especially high rates in diseases like COVID,” said study co-author Wes Ely, MD, MPH, co-director of the Center for Critical Illness, Brain Dysfunction, and Survivorship at Vanderbilt University Medical Center. “Delirium is depersonalizing in the moment and can lead to long-term dementia-like memory impairments that impair people’s recovery. We are working diligently to find solutions to improve quality of care and help people find healing in survivorship.”

Patients treated with tocilizumab experienced significantly more days without developing delirium or coma than patients who did not receive tocilizumab. And this was true regardless of whether tocilizumab improved patients’ other symptoms.

“This is very important and a much stronger effect than I expected,” Lahiri said. “It shows that the drug may have been a major factor in preventing delirium, and that patients weren’t just avoiding delirium because their COVID symptoms improved.”

Helping patients reduce the severity and duration of delirium, or avoid it altogether, could also help them avoid long-term cognitive effects, Lahiri said.

“We know that delirium, especially coma, is associated with significant long-term cognitive changes and is considered one of the few potentially modifiable risk factors for dementia,” Lahiri said. “Recent research concluded that delirium triples a patient’s risk for dementia and doubles the rate of decline in patients who develop Alzheimer’s disease.”

Lahiri has also studied delirium in patients with urinary tract infections, and found that estrogen treatment, like tocilizumab, was associated with lower levels of IL-6 and delirium. He said that many different conditions besides COVID-19 can cause IL-6 levels to go up and increase risk of delirium. In future studies, he would like to directly test tocilizumab in patients with acute respiratory distress syndrome.

“These findings extend the previously reported benefits of tocilizumab to include the potential for significantly reduced delirium or coma episodes in patients with severe COVID-19,” said Nancy L. Sicotte, MD, chair of the Department of Neurology, the Women’s Guild Distinguished Chair in Neurology and professor of Neurology at Cedars-Sinai. “Confirmation of these findings in randomized prospective studies may lead to new pharmacological options for preventing or reducing risk of delirium and coma for patients experiencing critical illness.”

Funding: Dr. Ely has received a research grant from Dr. Franz Kohler Chemie GMBH and is supported by the NIH grants (R01 AG027472, R01 AG035117, R01 AG058639, I01RX002992). Dr. Lahiri is supported by a research grant from the F. Widjaja Foundation.

Additional authors include Tuqa Alkhateeb, PharmD; Joanna L. Stollings, PharmD; Ine Sohn, MS; Dandan Liu, PhD; and L. Montana Fleenor, PharmD.

Read More in Discoveries: A Double-Edged Sword: Inflammation and Your Health

The findings were recently published in the American Journal of Human Genetics.

In total, investigators used data from more than 26,000 women with ovarian cancer and 100,000 women without the disease. Investigators then confirmed 27 risk regions—meaning areas within an individual’s genetic makeup—that could make women more susceptible to developing ovarian cancer.

“The big takeaway is that multiple genetic variants are associated with the risk of ovarian cancer, but the risks of each variant are small,” said Paul Pharoah, MD, PhD, professor and research scientist in the Department of Computational Biomedicine at Cedar-Sinai, and corresponding author of the study.

How to decipher this risk, however, comes down to genetics.

“We used a variety of bioinformatic approaches to identify multiple genes that are likely to be important in the biology of ovarian cancer risk,” Pharoah said.

The findings provide a framework for improving disease prediction and prevention, according to Pharoah and Michelle Jones, PhD, a study author and assistant professor and co-director of the Applied Genomics, Computation and Translation Core in the Department of Biomedical Sciences.

“In this study we have continued to learn more about how differences in our DNA sequence change the way our genes are expressed in a way that may lead to the development of cancer,” Jones said. “It took a large team of diverse scientists working together to make this project a success, with each bringing unique expertise to the challenge.” 

As a next step, the Ovarian Cancer Association Consortium is analyzing how best to combine the risk information from multiple-risk genetic variants.  

“We are particularly interested in optimizing polygenic risk models in women from diverse ancestries, which have the potential utility to identify women at high risk of ovarian cancer who may benefit from preventive interventions,” Pharoah said.

Other Cedars-Sinai investigators involved in the study include Simon G. Coetzee, Dennis Hazelett, Pei-Chen Peng and Marc T. Goodman.

The analyses presented in this manuscript have been funded in part by NIH/NCI grants: R01CA207456, R01CA204954, R01CA211707, R01CA211575, R01CA207456, R21CA220078, R00CA256519 and U19C8804/A7058. A proportion of funding was provided as part of an Institutional commitment to The Center for Bioinformatics and Functional Genomics at Cedars-Sinai Medical Center.

Read more from the Cedars-Sinai Newsroom: Cancer Epidemiologist Sees Collaboration As Key to Research Success

Thompson, professor of Medicine and co-leader of the Cancer Prevention and Control Program at Cedars-Sinai, was addressing the second graduating class in the Undergraduates Gaining Research Opportunities for the Cancer Workforce (U-GROW) internship program. Thompson is program director of U-GROW, and at the April 27 graduation event, students shared the ways in which many things, including their vocabulary, had changed since they entered the program during the summer.

The yearlong program, a partnership between Cedars-Sinai and eight California State University (CSU) campuses, gives participants an opportunity to intern with Cedars-Sinai Cancer investigators for nine weeks during the summer, conducting research and presenting their work during a scientific poster session. During the school year, they attend scientific communication workshops and receive guidance on applying to graduate and professional schools.

“For once I feel that I belong to a community,” said Agatha Santos, a CSU, Northridge, graduate now pursuing her master’s in public health. “I am working right now on a breast cancer pilot study with the Asian American population, which perfectly aligns with my interests, and if it wasn't for you, Dr. Thompson, I wouldn't have the confidence and the lingo to have that internship.”

Diana Martinez, a CSU, Los Angeles, graduate who interned with Thompson, was accepted into the master’s in public health program at the University of California, Berkeley, and awarded a fellowship that will fund her first year.

“I was really put to work and thrown into the water,” Martinez said, “but I really do appreciate it because it’s a realistic experience of what to expect when you’re in this field.”

Some of the participants, including Yzabella Nardo and Christina Gloady, were excited to contribute something meaningful to cancer research.

“My project was on medication delivery systems that release medication or chemotherapy directly into metastatic breast cancer cells to inhibit their growth,” said Gloady, a graduate of Cal Poly Pomona (California State Polytechnic University, Pomona) now applying to physician assistant programs. “I helped prove that this delivery system is more efficient and effective than other therapies currently on the market.”

The participants also expressed gratitude for the support of their peers in the program.

“Following the program into my first semester of organic chemistry, the class that everyone had hailed as the ruiner of dreams, when times got hard, I thought back to my peers of Cohort 2 and how many of them had already overcome the challenges that I was currently facing,” said Tyler Morris, a CSU, Long Beach, student. “It gave me the confidence to push through and succeed.”

Many of the students have entered or been accepted to graduate programs. And all have added to their academic and professional community—and their scientific vocabulary.

The program is funded by Cedars-Sinai Cancer and the Concern Foundation, and supported by Darrah Goo Kuratani, PhD, MPH, senior research project advisor, Cancer Research Training and Education Coordination.

Other U-GROW program faculty include Stephen Freedland, MD, the Warschaw, Robertson, Law Families Chair in Prostate Cancer at Cedars-Sinai and associate director for Training and Education at Cedars-Sinai Cancer; Katherine Isokawa, PhD, visiting scholar at Cedars-Sinai; Annalyn Valdez-Dadia, DrPH, assistant professor of Human Services at CSU, Dominguez Hills; and Sherry Kidd, U-GROW internship coordinator.

“Developing and promoting the next generation of cancer researchers is one of our core missions,” said Dan Theodorescu, MD, PhD, the PHASE ONE Foundation Distinguished Chair and director of the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute. “Among the multiple programs we have in the cancer center, U-GROW is one of our most important because it not only fulfills this mission, but does so for students who did not have as many such opportunities in the past. It is very gratifying for all of us to see this happen.”  

U-GROW has already selected CSU students for Cohort 3, beginning June 2024. The program will begin accepting applications for Cohort 4 on Nov. 1. Learn more about internship opportunities at Cedars-Sinai.

Cohort 2 (2023-2024) U-GROW scholars and mentors include:

• Iluoghene Akene, mentored by Christie Jeon, ScD
• Julianna Argueta, mentored by Jane Figueiredo, PhD
• Kathleen Bascos, mentored by Loraine Escobedo, PhD, MPH, and Ghecemy Lopez, DSW, MAEd
• Benito Cermeno, mentored by Stephen Shiao, MD, PhD, and Julie Jang, MD, PhD
• Naeomi Chin, mentored by Paul Pharoah, PhD
• Christina Gloady, mentored by Lali Medina-Kauwe, PhD
• Anakaren Gonzalez, mentored by Stephen Freedland, MD
• Liana Gutierrez, mentored by Gillian Gresham, PhD
• Savanna Monson, mentored by Jun Gong, MD
• Diana Martinez, mentored by Patricia Thompson, PhD
• Tyler Morris, mentored by Sarah Salvy, PhD
• Yzabella Nardo, mentored by Celina Shirazipour, PhD
• Horacio Palma, mentored by Geetanjali Datta, PhD, and Vanessa Torres, PhD
• Kenneth Perez, mentored by Margaret Liang, MD
• Agatha Santos, mentored by Kate Lawrenson, PhD

Follow Cedars-Sinai Academic Medicine on X for more on the latest basic science and clinical research from Cedars-Sinai.

The findings are published in The Journal of Infectious Diseases.

“Protection provided by infection wanes over time,” said Joseph Ebinger, MD, a clinical cardiologist, director of Clinical Analytics in the Department of Cardiology in the Smidt Heart Institute at Cedars-Sinai, and first author of the study. “These findings show that vaccination is still an important part of the arsenal for protecting people over the long term.”

Investigators tracked infections among 4,496 people who agreed to share serological samples as part of their participation in the study. From December 2021 to December 2022, when the Omicron variant was dominant, the investigators documented 2,053 new-onset infections in this group.

They examined incidence of new infections among people who were either infected less than 90 days prior or whose last known antigenic exposure was either recent (<90 days) or remote (≥90 days) infection or vaccination.

A key part of the study reviewed data from people whose most recent antigenic exposure was more than 90 days prior. For this group, people age 60 and older were significantly more protected by vaccination than prior infection.

“We know from previous studies by our group and others that the combination of prior infection and prior vaccination offers a hybrid immunity,” said Kimia Sobhani, PhD, associate professor of Pathology and Laboratory Medicine at Cedars-Sinai and senior author. “We wanted to understand whether if the last exposure was a long time ago, would it have been better if that last exposure was an infection or if it was a vaccination. Asking the question this way helps us understand if someone might benefit from another vaccination.”

The investigators are continuing to study the factors that can build and maintain immune memory against SARS-CoV-2 infection, even as the virus continues to mutate.

Other Cedars-Sinai investigators who worked on the study include Nancy Sun, MPS; Sandy Y. Joung, MHDS; John Michael S. Sanchez, MD, PhD; Minhao Wang, MPH; Yunxian Liu, PhD; Mallory Heath, MLS; Susan Cheng, MD, MPH; and Kimia Sobhani, PhD.

Funding: The study was funded by the Erika J. Glazer Family Foundation and Sapient Bioanalytics, LLC.

is the first step toward a better understanding of EV biology and the development of new clinical tests to measure disease progression in real time.

“Our hope is to be able to associate different EV fingerprints with different diseases and responses to treatment,” said Dolores Di Vizio, MD, PhD, professor of Urology, co-leader of the Cancer Biology Program at Cedars-Sinai Cancer and co-senior author of the study. “As cancer scientists, we are primarily interested in applying this new technology to the creation of ‘liquid biopsy’ tests for cancer detection. However, because all cells in the body produce EVs, we also envision its future use to identify biomarkers of cardiovascular disease, autoimmune diseases or neurological disorders.”

EVs are made of an outer envelope of fat molecules filled with “cargo” that might include RNA, proteins and lipids. The tiny particles vary greatly in size, with the largest being about one-tenth the width of a human hair.

“Prior to this study, EVs were mainly classified by their size and by how they were generated,” said Andries Zijlstra, PhD, adjunct associate professor of Pathology, Microbiology and Immunology at Vanderbilt University Medical Center and co-senior author of the study. “The goal of this study was to create a technology that could classify EVs based on several of their characteristics and their various combinations.”

EVs are studied using flow cytometry. The particles are separated from a blood sample, then suspended in fluid flowing through a laser beam that measures their physical and chemical characteristics.

To create the new technique of EV fingerprinting, investigators measured 20 different EV characteristics and used machine learning to classify various combinations of membrane composition, cargo, size and method of generation.

“The concept is that cells in different disease states will produce EVs with a unique fingerprint,” Di Vizio said. “For instance, we have prostate cancer cell lines, and each of these lines now has an EV fingerprint associated with it.”

A further advantage of EV fingerprinting is that it can be performed directly from a blood sample without the laborious process of separating out the EVs, Di Vizio said. This means the technology can be used to develop “liquid biopsy” tests that can be used in clinics.

“Our EV fingerprinting method is faster than most liquid biopsy approaches that require the isolation of EVs,” Di Vizio said. “These tests could be used for diagnosis, monitoring progression of disease and response to treatment, and perhaps even predicting patient outcomes.”

Investigators will next explore pairing specific EV fingerprints with specific disease states, beginning with aggressive forms of cancer, Di Vizio said.

“This type of translational science is key to our mission at Cedars-Sinai Cancer,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair and Director at the Samuel Oschin Comprehensive Cancer Institute. “By developing practical new testing techniques that allow us to precisely measure the state of a patient’s health, we can promote the concept of ‘precision prevention,’ expand the promise of precision therapy in oncology and save patients’ lives.”

Funding: This work was supported in part by grants from the National Institutes of Health (R01CA218526 to AZ and DDV; R01CA234557 to 1183 DDV; R01CA249424 to HP and AW; P01CA229123, R01CA206458, R01CA249684 and U01CA224276 to AMW) and the National Science Foundation (NSF-2328276 and NSF-2036809 to AMW and JTW).

Additional authors include Tatyana Vagner, Ariana K. von Lersner, Fabiane Fernandes, Patricia Midori Murobushi Ozawa, Marques Jackson, Matthieu Masureel, Hoangdung Ho, Sierra M. Lima, Tatyana Vagner, Bong Hwan Sung, Mohamed Wehbe, Kai Franze, Heather Pua, John T. Wilson, Jonathan M. Irish and Alissa M. Weaver.

Read more on the Cedars-Sinai Blog: Study Sheds Light on How Cancer Spreads in Blood

The idea for the joint symposia came from Ophir Klein, MD, PhD, executive vice dean of Children’s Health, executive director of Cedars-Sinai Guerin Children’s, and the David and Meredith Kaplan Distinguished Chair in Children’s Health. Klein developed the plan with Jeffrey A. Golden, MD, executive vice dean of Research and Education and director of the Burns and Allen Research Institute at Cedars-Sinai.

“When you look at the region, Cedars-Sinai and Caltech are two premier institutions that have a tremendous amount of potential synergy and not a lot of areas where we compete with each other,” said Klein, who gave a presentation about renewal in oral epithelia at the April 18 kick-off event on the Caltech campus. “There is a lot we can accomplish together that we likely cannot accomplish separately, whether it’s Caltech having access to translational and clinical expertise or Cedars-Sinai having access to their outstanding engineering and basic science."

During the Cedars-Sinai symposium on May 1, Klein welcomed one of the newest members to the Cedars-Sinai research community, David Traver, PhD. Beginning June 1, Traver will serve as director of a new developmental biology and regenerative pediatrics center at Guerin Children’s and as a professor in the Department of Pediatrics.

During the two events, leaders in their fields delivered scientific presentations. Cedars-Sinai presenters included:

• John Chute, MD, director of the Division of Hematology and Cellular Therapy and the Linda Ostrowski Chair in Hematology/Oncology in honor of Barry Rosenbloom, MD
• Helen Goodridge, PhD, professor of Biomedical Sciences and a research scientist in the Cedars-Sinai Board of Governors Regenerative Medicine Institute
• Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute and the Mark Siegel Family Foundation Distinguished Chair
• Margareta Pisarska, MD, director of the Division of Reproductive Endocrinology and Infertility and professor of Obstetrics and Gynecology
• Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine 

Speakers from Caltech included:

• Marianne Bronner, PhD, director of the Beckman Institute and the Edward B. Lewis Professor of Biology
• Michael Elowitz, PhD, the Roscoe Gilkey Dickinson Professor of Biology and Bioengineering
• Matt Thompson, PhD, assistant professor of Computational Biology
• Magda Zernicka-Goetz, PhD, the Bren Professor of Biology and Biological Engineering 

“Our institutions are both interested in how biology can go wrong to produce disease, but we come at it from different directions: Caltech begins with fundamental biology, while Cedars-Sinai begins with disease,” said Marbán, whose presentation focused on attenuation of DNA damage response by noncoding RNA drugs. “The opportunity to talk to each other will undoubtedly lead to powerful partnerships to improve human health.”

Presentations at the Cedars-Sinai symposium included topics such as the vascular control of hematopoietic stem cell regeneration (Chute), the use of synthetic biology to design circuits in cells to address biomedical problems (Elowitz), placentation and development of trophoblast cell lineages (Pisarska), and combining organ chip and stem cell technology to model human disease (Svendsen).

“These events brought together two institutions that are complementary, with a shared passion for discovery and application,” said Magda Zernicka-Goetz, PhD, who helped spearhead these newly launched events and also presented at the Cedars-Sinai symposium on building embryo models from stem cells. “I think that is why both symposia have been successful, because there is a dual passion for science and for application.”

Attendees also participated in a brainstorming session on how the two institutions can best partner. Ideas for further collaboration included visiting professorships, access to research cores at each institution, joint grant applications, shared postdoctoral and graduate student programs, and more networking-focused events and retreats.

“The speakers really highlighted the strengths of each institution: fundamental science at Caltech and translational science at Cedars-Sinai,” Golden said. “The brainstorming session also identified some wonderful ideas on how to move forward and future directions to solidify and strengthen an enduring partnership between the two institutions.”

Based on these sessions, Cedars-Sinai leaders—together with Bronner and Zernicka-Goetz—are planning upcoming events to bring together broader groups of investigators from each institution.

“I am hopeful that over time, we will have shared faculty, postdoc and student positions that leverage the science at both institutions,” Golden said. “We are putting in place processes to facilitate collaborations and use of each other’s strengths and resources. We are excited to see this collaboration mature.”

Follow Cedars-Sinai Academic Medicine on X for more on the latest basic science and clinical research from Cedars-Sinai.

The half-day scientific meeting opened with a presentation on the future of women’s health by Sarah Temkin, MD, the Associate Director for Clinical Research for the Office of Research on Women’s Health at the National Institutes of Health (NIH).

“We’ve understood for decades that women experience health and disease differently and that overall, they have a higher prevalence of diseases and more years lost to illness when compared to men,” Temkin said.

Studies that led to the development of therapies for a wide range of diseases usually left women and their biological differences out of the equation. That began to change in 1993 when the federal government mandated the NIH to include women, and racial and ethnic minorities, in funded trials. Since 2015, the NIH has required that study designs and analyses factor in sex as a biological variable, a term often abbreviated as SABV.

“Gender inequality is bad for the health of women and it’s also bad for the health of men and for society as a whole. The good news is that now, over 50% of our funded research meets that SABV criteria,” Temkin said.

But funding for women’s research remains a significant challenge. In 2023, NIH investments in women’s health amounted to about 10% of its $45 billion budget, with substantially more money spent on conditions that impact men, Temkin said.

“The federal government can play a key role in closing that funding gap by backing its Women’s Health Research initiative with meaningful funding. When you improve women’s health, you also improve the health of their families,” said Sarah Kilpatrick, MD, PhD, who holds the Helping Hand of Los Angeles Chair in Obstetrics and Gynecology and co-leads the CREWHS Steering Committee.

Private fundraising has a key role to play as well, said C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center in the Smidt Heart Institute and co-leader of the CREWHS Steering Committee.

“We need to emphasize the value of private seed funding, which can result in larger federal studies aimed at improving human health, especially in light of the stated commitment of first lady Jill Biden, who visited Cedars-Sinai and saw firsthand the institutional dedication to supporting women’s health research,” Bairey Merz said.

CREWHS’s funding goals for the next three years include seeking federal financing from the Women’s Health Initiative to support training and career development for emerging scientists investigating women’s health and sex differences, said Caroline Jefferies, PhD, an autoimmune disease scientist, associate professor of Medicine and Biomedical Sciences and the scientific director of CREWHS.

During the afternoon sessions, Martha Gulati, MD, director of Preventive Cardiology in the Department of Cardiology in the Smidt Heart Institute, presented her groundbreaking research showing that women get the same exercise benefits as men but with less effort.

“Women are not small men and they have not been studied well at all. But for our investigation, we got some good news for women related to outcomes and physical activity; less is more,” Gulati said.

The symposium concluded with nine investigators presenting results of their sex-differences research as part of the meeting’s “Lightning Talks” competition. The wide range of topics includes autoimmune disease, weight management interventions and gene expression in the human placenta. A monetary award was offered for the best study and presentation. Project scientist Predrag Jovanovic, PhD, received the reward for his investigation of how scents that induce a stress response moderate metabolism based on gender.

CREWHS 2024 Funding

The CREWHS Steering Committee is now accepting research applications for the 2024 CREWHS Awards for pilot projects seeking seed funding for the investigation of women’s health and sex differences. Those selected will receive up to $50,000-$100,000 (direct costs) for a year, with a potential to extend for a second year.

Email groupwomenshealthresearchadmin@cshs.org for more information. Applications are due by Friday, June 14, 2024.

Follow Cedars-Sinai Academic Medicine on X for more on the latest basic science and clinical research from Cedars-Sinai.

Guest speakers included Suzanne Devkota, PhD, director of the new Human Microbiome Research Institute and associate professor of Medicine and Biomedical Sciences, and Mahendra Yatawara, associate director of Research Informatics in EIS’ Research Informatics and Scientific Computing Core.

New Human Microbiome Research Institute

Devkota outlined the twofold mission of the Human Microbiome Research Institute.  

“We aim to reduce barriers to entry in microbiome-based research through technical, educational and collaborative programs,” she said. “We also want to advance the microbiome field by generating mechanistic, human data across disciplines that leverage the unique strengths of the relationships between clinicians and basic scientists at Cedars-Sinai.”

Devkota also reviewed the goals of the program, including:

• Supporting microbiome research needs for faculty and trainees through expanded core infrastructure.
• Educating the research community in microbial sciences through workshops, seminars, dedicated consultations and internships.
• Innovating in key areas of microbiome science through tool development, industry partnerships and commercialization. 

The expanded offerings include several services and resources important for microbiome research, which Devkota encouraged faculty and their colleagues to engage. Those include germ-free and gnotobiotic mice, microbiome sequencing, bacterial cultivation and archiving, study design consultation, and sample procurement.

Resources Offered by Research EIS Team

Yatawara’s presentation shared information on the many available resources offered by the Research EIS enterprise to support Cedars-Sinai investigators. 

“I encourage researchers with specific needs who feel that there are technologies and tools that are absent at the organization to please reach out to me so we can collaborate to better understand and support all investigators,” said Yatawara. “Many research tools and technologies can be acquired in bulk, enabling the transfer of cost-savings back to the researcher. For special research projects that require nonstandard technologies, we encourage partnering with us to ensure that researchers do not face any specific delays or roadblocks along the way.”

Scheduling an up-front consultation with EIS Research, Yatawara said, would provide many efficiencies in allowing the team to guide researchers on the appropriate path.

The EIS Research team consists of data, programming, application and systems professionals who are dedicated to supporting and advancing the research efforts happening at Cedars-Sinai. The team collaborates with all EIS teams to deliver technology and service priorities that are defined by both the Strategic Prioritization Council and the EIS Advisory Committee.

Research applications and technologies offered through EIS Research include:

• Service Center: offers search and an EIS knowledge base for all IT-related items at https://servicecenter.csmc.edu
• EIS Research intranet site: offers a comprehensive listing of all services at https://intranet.cshs.org/sites/EISResearch
• High-performance computing (HPC): a total of four clusters comprising 5,406 cores, 26 GPUs, and 88.3 TB of RAM and producing over 450 TFLOPS of processing capability
• Research storage and virtual servers: offer over 5 petabytes of Isilon storage with redundancy available for research; cloud storage on Amazon Web Services, with short-term and long-term storage availability; data cataloguing, moving and automation via Starfish software, with per-user and per-lab reporting; and Microsoft OneDrive storage in HIPAA compliant environment
• Clinical trials management through OnCore: a secure, web-based, comprehensive system for managing clinical trials
• Search Clinical Trials: a tool that allows patients to search for active clinical trials available at Cedars-Sinai. The website is publicly available and can be found at https://clinicaltrials.cedars-sinai.edu
• LabVantage: a powerful lab information-management system that integrates with instruments and systems to enable proactive biospecimen data management and monitoring
• Los Angeles Data Resource: providing de-identified patient counts from five organizations—including Cedars-Sinai, UCLA, University of Southern California, City of Hope and Children’s Hospital Los Angeles—as well as data inclusive of demographics, ICD codes, medications and labs
• Deep 6: artificial-intelligence software that analyzes structured and unstructured CS-Link data, as well as physicians’ notes, pathology reports and surgical notes
• eRegulatory–Florence eBinders: an industry standard eRegulatory solution for clinical trial recordkeeping. The platform simplifies and streamlines the process for managing trial documents, allowing users to organize, track and access trial records securely over the internet. It can be found at https://researchbinders.com
• SymplecticElements: allows academic faculty to build a public profile by aggregating all their research outputs—publications, grants, and professional and teaching activities. It can be found at https://researchers.cedars-sinai.edu

CS-IACUC Launches June 3

Golden also gave attendees several logistical updates, including a reminder about the introduction of the new Institutional Animal Care and Use Committee (IACUC) program, CS-IACUC. Beginning June 3, the new system will replace the current Webridge IACUC platform.

Key details about CS-IACUC:

• Wednesday, April 24, is the final deadline for new study submissions in Webridge. Studies submitted by this deadline will be on track for review at the May IACUC meeting.
• Studies in Webridge that are not submitted by April 24 must be entered in CS-IACUC after Monday, June 3, and submitted by the Friday, June 14, deadline for the July IACUC meeting.
• No new amendments will be accepted in Webridge between Friday, May 3, and Monday, June 3.
• Training sessions are scheduled, and questions should be directed to Ajay Sagar at ajay.sagar@cshs.org.

“We identified a new subtype of cells surrounding therapy-resistant soft tissue sarcomas,” said Jlenia Guarnerio, PhD, a research scientist at Cedars-Sinai Cancer and senior author of the study. “These cells secrete a molecular ‘Velcro’ called CXCL16 that traps immune cells, especially T cells, and keeps them from entering the tumor. With very few T cells inside the tumor, available immunotherapies aren’t effective.”

Soft tissue sarcomas originate in muscle, fat, blood vessels, nerves, tendons and joint lining, and can occur anywhere in the body. Some of these tumors do not respond to immunotherapy, which helps the body’s own immune system fight cancer cells, said Marina Broz, a PhD student in the Guarnerio Lab at Cedars-Sinai and first author of the study.

“Previous studies have shown that cells called cancer-associated fibroblasts prevent immune cells from entering these tumors, leading to therapy resistance, but the way they achieve this is poorly understood in many cancers and particularly in soft tissue sarcomas,” Broz said.

Investigators found a particular subtype of cancer-associated fibroblasts surrounding therapy-resistant soft tissue sarcomas in laboratory mice.

“These are the cells that are trapping T cells outside the tumors,” Broz said. “And we noted that they rely on glucose to make energy, which turned out to be the key to turning non-responding tumors into responders.”

When investigators treated the mice with a glycolysis inhibitor to stop the cells from using glucose, the fibroblasts no longer secreted CXCL16—and T cells invaded the previously therapy-resistant tumors. This dramatically improved the abundance of T cells, thus making the tumors more vulnerable to chemotherapy as well.

“Without the inhibitor, the tumors were barely responsive to therapy,” Guarnerio said. “The inhibitor alone didn’t reduce tumor growth at all, but in combination with chemotherapy it significantly reduced tumor growth.”

Because glycolysis inhibitors aren’t safe for patients, investigators will work to develop a therapy to target CXCL16, said Guarnerio, who is also an assistant professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai.

“Targeting CXCL16 could also improve outcomes for patients with other types of immunotherapy-resistant tumors,” Guarnerio said. “We would like to see if we can engineer a therapy to improve treatment response in all tumor types with poor T cell infiltration.”

Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair, said that the study is an example of translational research that may produce targeted therapies.

“This work represents our commitment at Cedars-Sinai Cancer to the promise of precision medicine, which may produce targeted therapies and further enhances our clinical adult and pediatric sarcoma program,” Theodorescu said.

Additional Cedars-Sinai authors participating in this study included Emily Y. Ko, Kristin Ishaya, Jinfen Xiao, Marco De Simone, Xen Ping Hoi, Roberta Piras, Basia Gala, Fernando H. G. Tessaro, and Anja Karlstaedt.

Other authors included Sandra Orsulic, Amanda W. Lund, and Keith Syson Chan.

Funding: J.G. was supported by the K99/R00 grant (CA212200) and R01 (CA258265) for the execution of this work. Additionally, J.G. was supported by grants from the Sarcoma Foundation of America (Grant 2019 SFA 15–19), and the Cedars-Sinai Cancer Accelerator Award. M.B. was supported by a National Cancer Institute F31 fellowship (1F31CA284888). K.S.C was supported by R01CA175397, R01CA175397-Supplement, U54CA274375. X.P.H received funding from U54CA274375. A.W.L. received support from the Cancer Research Institute (Lloyd J. Old STAR Award). A.K. was supported by the National Heart, Lung and Blood Institute (R00 HL141702) and the Leukemia Research Foundation New Investigator Award (Grant No. 941997).

Read more on the Cedars-Sinai Blog: Immunotherapy – The Fourth Pillar of Cancer Care

The Rutishauser Lab collaborates with several leading universities and medical centers, including the California Institute of Technology, Johns Hopkins University, the University of Toronto, Boston Children’s Hospital and the University of Colorado at Denver. A key aspect of this collaboration is open data-sharing. Cedars-Sinai is part of the National Institutes of Health BRAIN Initiative Research Opportunities in Humans Consortium, representatives of which recently penned an article for the peer-reviewed journal Neuron on the benefits of data-sharing.

“Dr. Rutishauser’s work advances our understanding of the workings of the human brain and also connects Cedars-Sinai with top medical institutions across the country and beyond,” said Jeffrey Golden, MD, vice dean of Research and Research Education at Cedars-Sinai. “Work of this caliber simply isn’t possible if institutions guard their discoveries and data, encumbering collaboration.”

Rutishauser, who holds the Board of Governors Chair in Neurosciences, sat down with the Cedars-Sinai Newsroom to discuss the role of data-sharing and scientific collaboration in his work and the broader scientific community.

What type of data does your lab’s research generate, and how has it advanced our understanding of the human brain?

Our data is acquired from patients with epilepsy who are undergoing depth-electrode monitoring, which means they have tiny electrodes surgically inserted into the brain to monitor seizure activity.

We use these recordings of the electrical pulses sent between individual neurons within the brain to study how the brain records and recalls memories, how we make decisions, and how these processes go wrong under certain conditions. For example, we have discovered how we monitor our own behavior for errors using this approach.

The same data, which is rare and difficult to acquire, can also be used to study many other aspects of the human brain, but this is only possible if the data is made accessible to other investigators inside and outside of Cedars-Sinai.

What is the current state of data-sharing in human neuroscience?

Funding agencies and journals require that research teams make their data available to others. However, they require sharing of only the exact data needed to reproduce a given study, often only on request.

This requirement is often viewed as a burden by investigators. But in our recent editorial, we point out the many benefits of investigators sharing all of their data freely and in a standardized format, so it is easily accessible. We found that when we, as the data producer, released data in this way, we discovered new collaborators who used our data to explore questions we had never thought about. Within our own lab, using a standardized data format also facilitated reuse of that data. And schools and universities have even used the data for teaching purposes.

Why is cross-institutional collaboration so important to the future of science?

Collaborating and sharing data is a way for us to broaden our impact. One of the inherent difficulties of the work I do is that the experiments are challenging to perform and the number of patients available is limited. To increase the amount of data available, we collaborate with research groups at other institutions. This allows us to perform large, well-powered studies and increases confidence in our findings by replicating findings at other institutions.

What challenges need to be overcome to increase data-sharing in neuroscience?

There are three challenges. First, the field has to agree on a standard data format. While there are formats that could fill this requirement, there’s no universal agreement on which should be the standard format. The use of a single standard data format in the field of neuroimaging, for example, shows the immense benefits of the practice. Second, we need data archives where very large files can be uploaded, stored and made available. Third, and perhaps most challenging, investigators must be willing to openly share their data.

What is your advice for investigators who want to share their data?

I strongly advise using a standardized data format. We chose to use the Neural Data Without Borders (NWB) format. Develop an expectation in your lab that when a project is finished, your team will export the data in that format, document it and publicly release it upon publication.

Jeffrey A. Golden, MD, executive vice dean of Research and Education at Cedars-Sinai, and Kenneth E. Bernstein, MD, professor of Pathology and Laboratory Medicine, welcomed attendees and introduced Liu, who visited Cedars-Sinai from Boston.

A Compelling Keynote

Liu is the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare, vice chair of the faculty at the Broad Institute of Massachusetts Institute of Technology and Harvard University, the Thomas Dudley Cabot Professor of the Natural Sciences at Harvard University, and a Howard Hughes Medical Institute investigator. According to Bernstein, Liu also is a bonsai tree enthusiast, woodworker, and dynamite poker player. 

Best known for his pioneering research in the engineering, evolution, and in vivo delivery of genome editing proteins—such as base editors to study and treat genetic diseases—Liu detailed several studies conducted in his laboratory. His work has influenced the understanding of proteins with novel therapeutic potential leveraging a methodology he pioneered, phage-assisted continuous evolution. His lab also focuses on the discovery of bioactive synthetic small molecules and synthetic polymers using DNA-templated organic synthesis and DNA-encoded libraries.

“The work happening now is moving us closer to clinical treatments for patients,” Liu said.

Attendees walked away from the keynote address with two major takeaways:

• Base editing rescues sickle cell disease, progeria and spinal muscular atrophy in animals by correcting the cause of each genetic disease.
• Prime editing enables versatile and efficient therapeutic substitutions, insertions and deletions in animals including primates.

Investigators Present Findings

Following the keynote address, more than 120 Cedars-Sinai investigators showcased research projects they developed at Cedars-Sinai.

One participant, Madelyn Arzt, a research associate III in the Sharma Laboratory, a member of the Board of Governors Regenerative Medicine Institute, presented an abstract titled, “Growth and Transfection of Human-Induced Pluripotent Stem Cells in Commercially Available Culture Plates During a Private Spaceflight Mission.”

The project overall, Arzt said, evaluates whether induced pluripotent stem cells could be manufactured in space by astronauts. More recently, their research evaluated whether the microgravity conditions in space can improve stem cell production. She joined colleagues from the Sharma Laboratory when they traveled to Florida in May 2023 to see a space mission take off with Cedars-Sinai’s stem cells aboard.

Research Day, Arzt said, is another important step in her journey to earning her doctorate and eventually running a lab, like her mentor, Arun Sharma, PhD.

“Research Day is such a great way to get exposed to the breadth of research being conducted across departments and institutes. It also fosters communication and collaboration with so many other individuals you may not get an opportunity to interact with daily,” Arzt said. “I am eager to make these connections that facilitate further collaborations with my colleagues.”

Award-Winning Work

Noel Bairey Merz, MD, director of the Barbra Streisand Women's Heart Center in the Smidt Heart Institute and principal investigator of the National Institutes of Health Microvascular Aging and Eicosanoids - Women's Evaluation of Systemic Aging Tenacity (MAE-WEST) Specialized Center for Research Excellence (SCORE), recognized two researchers with the “Sex as a Biological Variable Award." The award recognizes investigators whose research incorporates sex differences into the design and analysis of their research.

“In the classroom and in their training, our investigators learn how to develop research questions and study designs specific to sex differences in both females and males,” Bairey Merz said. “It’s critically important for women’s health because so often either male animals or male cells have been preferentially studied, which doesn’t allow for precision medicine opportunities for either sex.”

Amelia Andrews, a research associate I in the Goodridge Laboratory, also a member of the Board of Governors Regenerative Medicine Institute, received first place for her abstract titled “Roles of Sex Chromosomes and Gonadal Hormones in Monocyte and Macrophage Sex Dimorphism.” 

Tania Gonzalez, PhD, a postdoctoral scientist in the Pisarska Laboratory in the Department of Obstetrics and Gynecology, received second place for her abstract titled, “First Trimester Human Placenta DNA Methylation Correlates to Maternal Estradiol Levels.”

“I’m really honored to receive this recognition of our work,” said Andrews. “The poster session was a great opportunity to get feedback and ideas for future studies from other investigators. Macrophages are thought to be the most sex dimorphic immune cells and I’m excited to be studying the fundamental mechanisms underlying their influence on inflammation and human disorders.”

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai.

A ceremony on March 5 in Tel Aviv was led by Shlomo Melmed, MB, ChB, executive vice president for Medicine and Health Sciences and dean of the Medical Faculty at Cedars-Sinai, and professor Ronni Gamzu, CEO of Tel Aviv Sourasky Medical Center.

“By leveraging the strengths and expertise of each of our health systems, this partnership paves the way for groundbreaking research, spurs innovative treatments and enhances patient care on a global scale,” Melmed said. “We look forward to building a tradition of mutual research and educational opportunities for our physicians and scientists.”

The initial research efforts in the partnership are big data science, regenerative medicine and stem cell therapy, proteomics, endocrinology, and oncology. Investigators from both institutions who specialize in these areas are working together to identify opportunities to share resources and data leading to new research projects.

The partnership, Gamzu said, is not just between friends in hospitals, but between countries.

“I look forward to seeing how Tel Aviv Sourasky Medical Center, together with Cedars-Sinai, will bring innovation and shape the next generation of leaders and talented individuals who will help patients from all over the world,” said Gamzu.

And, in addition to advancing research and clinical collaborations, Melmed said the relationship with Tel Aviv Sourasky Medical Center offers an opportunity to advance technology startups in expanded markets.

“Together, we are poised to impact the lives of patients globally,” said Melmed.  

Over the past 20 years, Cedars-Sinai has developed fruitful relationships with health systems and medical centers in Israel, including with Sheba Medical Center, a 2,000-bed hospital located outside Tel Aviv. The relationship began as a collaboration aimed primarily at advancing cardiovascular medicine and the field of interventional cardiology.

Current joint research projects with Sheba Medical Center include developing treatments for pancreatic cancer, advancing research findings into treatments for patients with inflammatory bowel disease, launching stem cells into space and expanding digital pathology diagnostics.

“Today our partnership has grown into a large research and translational enterprise, with shared resources and joint research databases used to advance research,” said Harry Sax, MD, professor and executive vice chair of Surgery and associate dean for International Academic Programs at Cedars-Sinai.

Sax said Cedars-Sinai has welcomed visiting Israeli trainees, and soon, Cedars-Sinai hopes to send its own trainees as visiting scholars in Israel. These collaborations, he said, will also allow investigators to better understand why the same disease—like breast cancer or Crohn’s disease—presents differently for patients in Israel versus the United States. 

“The exchange of ideas between countries, coupled with computational biomedical techniques, will foster growth in unparalleled ways,” Sax Said. “Medical centers in Israel have a high level of energy and flexibility to advance medicine. Our mutual environments are ripe for innovation, and we are grateful to partner alongside esteemed medical centers in the country.” 

Inset Photo Caption: Research signing participants toast after the signing ceremony. From left to right: Professor Eli Sprecher, vice president of Research & Development and Innovation at Tel Aviv University, professor Karen Avraham, dean of the Tel Aviv University’s Faculty of Medicine, Melmed and Gamzu. Photo courtesy of Tel Aviv Sourasky Medical Center.

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai.

, and colleagues organized a meeting in Cambridge, UK, to bring together researchers from around the world studying the genetics of ovarian cancer. It led to the creation of the Ovarian Cancer Association Consortium (OCAC). Nearly 20 years later, the collaborating scientists are still working together.

“Almost everything we know about the genetics of ovarian cancer has come from this consortium, and that's involved working together,” he said.

Now, as professor and research scientist in the Department of Computational Biomedicine since 2022, Pharoah aims to work with colleagues across departments and laboratories at Cedars-Sinai to make similar inroads in tough-to-treat diseases.

Pharoah was previously professor of Cancer Epidemiology at the University of Cambridge where he led a research group studying how the genetic variants that people inherit alter risk for hormone-related cancers, and how patient and tumor characteristics affect chances of survival after a diagnosis of cancer. His research into prognostic factors led him to create two online tools that help clinicians make treatment decisions: PREDICT Breast Cancer and PREDICT Prostate. His work was recognized with the John Graunt Prize for Extraordinary Achievement in Population Sciences in 2016.

Pharoah spoke with the Cedars-Sinai Newsroom about new collaborations he looks forward to forming.

What has made your collaborations possible?

OCAC has been successful because we all shared the same vision for the sort of science we wanted to do, and we were willing to share data to make it happen. My team has collaborated with investigators from Cedars-Sinai for years, which is part of the reason I came here. Simon Gayther, PhD, was one of the founding members of OCAC, and Michelle Jones, PhD, joined seven years ago. In the past seven years, we have worked very closely on several consortium projects and the OCAC database is now hosted by us at Cedars-Sinai.

What inspired you to create the PREDICT websites?

I wanted to apply data on how different cancers behave and how people respond to treatment to develop tools to help oncologists personalize their approaches and guide their discussions with patients. The tools can explain the probabilities of a patient surviving depending on the treatment they get, and how different combinations of treatments might affect those percentages.

What projects are you currently working on?

My colleagues in Computational Biomedicine and I will develop the PREDICT tools further so they can incorporate data from a more diverse population than the initial data from the UK model.  

We're particularly interested in seeing how well the PREDICT Breast Cancer tool performs with women of African ancestry and women of Latin ancestries. One of our plans is to incorporate U.S. national data and data from Cedars-Sinai.

Looking ahead, what excites you most about the clinical applications of cancer epidemiology?

On the ovarian cancer genetics front, I would hope that in the next few years, with all the whole genome sequencing data that's becoming available from various biobanks around the world, we'll be able to use those data to continue to unravel the inherited basis of ovarian cancer.

We would like the opportunity to expand the PREDICT model into other cancers. There is a team in the UK working on kidney cancer prediction, and there's potential for doing work on colorectal cancer.

I'm also enjoying work on molecular pathology. We would like to start using some of the newer techniques such as spatial transcriptomics and spatial proteomics to investigate more complex patterns in the molecular pathology of ovarian cancer, and how they relate to clinical outcomes. We are particularly interested in studying the role of tumor immune cells.

When it comes to ovarian cancer, what we understand about the biology says patients should respond to immunotherapy, but, in fact, they often don't. There is work to be done in understanding what it is about the immune environment in this cancer that prevents response to immunotherapy. This is an area of research that is developing rapidly.

Follow Cedars-Sinai Academic Medicine on X for more on the latest basic science and clinical research from Cedars-Sinai.

The findings, published in Arteriosclerosis, Thrombosis, and Vascular Biology, suggest that a treatment therapy that inhibits interleukin-1-beta might help patients, including the approximately 20% of children who don’t respond to current therapies.

Kawasaki disease was first described by Japanese pediatrician Tomisaku Kawasaki in 1967, but its cause remains unknown. The condition typically affects children under the age of 5, and patients with the disease usually present with a sudden, high fever; rash; redness of eyes, lips and tongue; and swelling of hands and feet that last for 10 days or longer.

In Japan, Kawasaki disease cases are on the rise after a significant decrease in 2020.

“The disease is treatable in most children if caught early, but some children continue to have fever and become at risk of developing cardiovascular complications, such as coronary artery aneurysms or arrhythmias,” said Moshe Arditi, MD, executive vice chair of the Department of Pediatrics for Research at Cedars-Sinai Guerin Children’s, the GUESS?/Fashion Industries Guild Chair in Community Child Health, and a co-senior author of the study.

The standard of care for children with Kawasaki disease is to administer intravenous immunoglobulin and aspirin to reduce inflammation and fever. But recent clinical trials have found that blocking proteins called inflammatory cytokines, such as tumor necrosis factor alpha or interleukin-1-beta, improves symptoms in children.

Drugs that block tumor necrosis factor alpha are already being used in patients. A potential new therapy currently being investigated, anakinra, suppresses and blocks the function of the interleukin-1 receptor, which binds the inflammatory interleukin-1 cytokines.

This study sought to identify which cytokines might be involved in the biologic processes that cause cardiovascular complications in children with Kawasaki disease.

Arditi, who is also director of the Infectious and Immunological Diseases Research Center in the Department of Biomedical Sciences and a professor of Pediatrics, and Eugenio Cingolani, MD, who is director of Cardiogenetics and Preclinical Research at the Smidt Heart Institute at Cedars-Sinai and an associate professor of Cardiology, brought their labs together to work on the study.

Together, the investigators studied publicly available datasets showing gene expressions in children with Kawasaki disease. They found elevated expression of the genes of cytokines interleukin-1-beta and tumor necrosis factor alpha in patients with the disease.

“We sought to identify whether one protein caused more cardiac dysfunction and arrhythmias in this mouse model of Kawasaki disease,” Cingolani said.

The team performed several experiments in laboratory mice with a disease model resembling Kawasaki disease in humans. The investigators injected mice with drugs that block the expression of interleukin-1-beta or tumor necrosis factor alpha. They found that drugs that blocked interleukin-1-beta signaling but not tumor necrosis factor alpha signaling prevented abnormal changes in how the heart pumps blood and the heart’s rhythm. 

“We need to test whether these observations in an animal disease model remain true in children with Kawasaki disease,” said Thassio Ricard Ribeiro Mesquita, PhD, a research scientist with the Smidt Heart Institute, an assistant professor of Cardiology at Cedars-Sinai and first author of the study. “If so, they would further support the use of therapies that block interleukin-1-beta in patients with Kawasaki disease.”

Based on the experimental studies from the Arditi Laboratory on the role of interleukin-1-beta in Kawasaki disease, anakinra—the drug that blocks the interleukin-1 receptor—is now in Phase III clinical trials in children.

Other Cedars-Sinai investigators who worked on the study include Shuang Chen, Youngho Lee, Rodrigo Miguel-dos-Santos, Asli Atici, Magali Noval Rivas and Yen-Nien Lin.

The study was funded by the National Institutes of Health, the American Heart Association, the California Institute for Regenerative Medicine and the Cedars-Sinai Board of Governors.

Follow Cedars-Sinai Academic Medicine on X for more on the latest basic science and clinical research from Cedars-Sinai.

could help physician-scientists who obtain patient consent to extract information from these patients’ pathology reports for research and clinical trial recruitment.

“Cancer is a complex disease, and rich information is contained in the notes that a pathologist makes when they review a patient’s cancer underneath the microscope,” said Nicholas Tatonetti, PhD, vice chair of Operations in the Department of Computational Biomedicine at Cedars-Sinai, associate director of Computational Oncology at Cedars-Sinai Cancer and senior author of the study. “But because these notes are in the form of scanned PDFs, the text they contain has been inaccessible to computers—until now.”

To create a machine-readable pathology dataset, Tatonetti and his team worked with The Cancer Genome Atlas, a publicly available collection of information from thousands of U.S. cancer patients who have given permission for investigators to examine their personal health records.

“The pathology reports in the atlas are scanned in at all angles and in different formats from each of the institutions that provided them,” Tatonetti said. “They’re messy and their scan quality is relatively poor—not unlike pathology forms you would find in patient records.”

Investigators used AI to clean up the scans so that optical character recognition software could turn them into machine-readable notes. When investigators compared these notes against the original reports, they found this method was highly accurate.

“By making the reports machine readable, we can train algorithms to extract information from them in response to investigators’ questions,” Tatonetti said. “This will help investigators identify and validate new disease markers, conduct research, and recruit patients for clinical trials.”

The resulting collection of text from the reports, now publicly available, includes data on almost 10,000 cancer patients. The format is commonly used in machine learning to allow computational biologists and computer scientists to use the data, Tatonetti said. The method could also be used to extract pathology report data from other datasets.

“The true story of a patient’s condition, such as detailed information about their cancer and the effects of various therapies, is found in clinicians’ notes,” said Cedars-Sinai Cancer Director Dan Theodorescu, MD, PhD, the PHASE ONE Foundation Distinguished Chair and Director at the Samuel Oschin Comprehensive Cancer Institute. “Tools that help us mine this information further our efforts to conduct translational studies that bring the promise of precision medicine to each of our patients.”

Tatonetti and his team are now focused on training models to extract specific information—such as cancer staging—from the data.

“Our model can extract that information when it is present in the notes, but it can also accurately infer the stage when it is not explicitly stated,” Tatonetti said. “For instance, the pathologist might make a note about a secondary lesion or about or evaluating a sample of a breast cancer from the liver. These notes don’t include the word metastatic, but they do imply it.”

The team is also working to apply its method to the Molecular Twin Precision Oncology Platform, a unique precision medicine and AI tool created at Cedars-Sinai that includes pathology reports and other data on the majority of Cedars-Sinai’s cancer patients. Team members are also developing tools to make other clinician notes from patient records machine readable, Tatonetti said.

“AI enhancements to optical character recognition are the key to extracting a wealth of data from some of the most clinically relevant portions of patient records,” said Jason Moore, PhD, chair of the Department of Computational Biomedicine at Cedars-Sinai. “This data will fuel new studies by researchers across specialties, including research clinicians, clinical trial investigators and investigators working to improve tools that allow computers to interpret clinical language.”

Funding: This work was supported by National Institute of General Medical Sciences of the National Institutes of Health grant number R35GM131905.

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai.

Atrial fibrillation is an irregular heart rhythm that begins in the upper part of the heart. It is the most common type of arrhythmia.

“Once somebody has persistent AFib, our ability to put them back into a normal rhythm with ablation and medications is lower,” said Christine Albert, MD, MPH, chair of the Department of Cardiology, the Lee and Harold Kapelovitz Distinguished Chair in Cardiology, and senior and corresponding author of the study. “In addition, several studies suggest that once you have persistent AFib, you may actually have a greater risk for stroke, heart failure and dying from cardiovascular disease.” 

This more recent study found that risk factors for new-onset, persistent AFib include being older, male, overweight, having a higher BMI (≥30 kg/m2) and, interestingly, having post-college education.

Investigators theorized that the association between higher levels of education and persistent AFib may be related to people with greater health literacy being able to more easily access healthcare services. This correlation is presumed to make those with a higher education more likely than people with less education to receive an ECG, which can detect asymptomatic, persistent episodes of AFib.

The findings were released as part of a sub-analysis of the VITamin D and OmegA-3 TriaL (VITAL), an ongoing study investigating whether daily dietary supplements of vitamin D3 or omega-3 fatty acids reduce risk for developing cancer, heart disease or stroke.

For this sub-analysis, investigators examined associations in lifestyle, clinical and socioeconomic risk factors among more than 25,000 people without a history of cardiovascular disease, AFib or cancer.

Over the course of 5.3 years, 900 participants developed AFib and 346 (38.4%) had persistent AFib at the time of diagnosis.

“As cardiologists, we tend to think that we have some time, that we can intervene and prevent this particular type of atrial fibrillation,” Albert said. “This data suggests a substantial percentage of patients present this way, so it’s important to think about risk factor modification in the population that does not yet have known AFib, but who are at risk for developing AFib in the future.”

Albert said more trials are needed to learn how weight loss interventions might prevent people from developing persistent AFib.

“This research shows which groups of people might be most at risk for developing persistent AFib,” Albert said. “You could design a screening study targeted toward those populations to see if you could pick up atrial fibrillation sooner, so that it can be treated.”

Other Cedars-Sinai investigators who worked on the study include Melissa Middeldorp, PhD, MPH; Roopinder Sandhu, MD, MPH; and Jessica Mao, MD.

Funding: The VITAL Rhythm Trial was supported by R01HL116690, and the VITAL Trial was supported by grants U01 CA138962 and R01 CA138962, which included support from the National Cancer Institute, National Heart, Lung and Blood Institute, Office of Dietary Supplements, National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health of the National Institutes of Health.

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai.

The findings of the single center randomized controlled trial are published in Scientific Reports.

“We found that Cedars-Sinai patients in the P.A.I.N.-Sparing group received significantly less opioids and had greater physical activity during their hospitalization, when compared with IBD patients whose pain was treated with as-needed opioids. Also, those receiving the P.A.I.N. protocol tended to have lower overall pain scores while in the hospital,” said Gil Melmed, MD, principal investigator of the study and director of Inflammatory Bowel Disease Clinical Research at Cedars-Sinai.

The P.A.I.N.-Sparing treatment approach developed by investigators was based on a review of the literature on pain management and included scheduled, non-opioid pain medications tailored to the severity of a patient’s reported discomfort. Melmed said that if this approach were not sufficient to control pain, the IBD patients could request opioid pain medications, as needed.

Inflammation, severe diarrhea, malnutrition and acute and chronic pain are leading causes of repeat hospitalizations for IBD patients. Pain is rated by these patients as one of the most burdensome aspects of the disease, yet there is insufficient evidence to support a pain management strategy that is effective.

“Opioid use is more prevalent in IBD than in any other chronic gastrointestinal condition. In spite of the widespread use of these medications, our previous studies have found that opioids do not meaningfully reduce the pain these patients experience. Additionally, there are the known risks associated with using these medications for chronic conditions, including misuse, overdose, infection, hospital readmission and even death,” said Melmed, a professor of Medicine.

Larger, multicenter trials would be useful to further validate the efficacy of the P.A.I.N.-Sparing protocol for IBD patients, Melmed said. He is also encouraged by the emergence of new tools for managing pain.

“There are novel, non-pharmacologic strategies being rigorously studied for their potential to control acute and chronic pain. Biofeedback, virtual reality and other modalities could be incorporated into a proactive approach for addressing the pain and quality of care of our hospitalized IBD patients,” Melmed said.

Additional (current) Cedars-Sinai investigators: Devin Patel, MD; Rajalakshmi Govalan, MD; Shao-Chi Greg Huang; Catherine Bresee; and Teryl K. Nuckols, MD.

Follow Cedars-Sinai Academic Medicine on X for more on the latest basic science and clinical research from Cedars-Sinai. 

at Cedars-Sinai aimed to understand the possible connection between COVID-19 vaccination and a difficult-to-diagnose heart condition called postural orthostatic tachycardia syndrome, or POTS. The study validated that patients who were immunized with a COVID-19 mRNA vaccination and then went on to have new or exacerbated POTS all had preexisting conditions that can lead to a POTS diagnosis.

POTS is associated with nervous system dysfunction and causes an abnormal increase in heart rate after standing or sitting up. It used to affect primarily women of childbearing age. However, for POTS cases that developed during the COVID-19 pandemic, men were equally affected.

“We were surprised when all the patients in our small cohort already had conditions that could make them more likely to develop POTS even without vaccination, such as palpitations, fast heart rates, orthostatic intolerance, hypermobile joints, asthma, systemic lupus, fainting and chronic abdominal pain,” said Peng-Sheng Chen, MD, the corresponding author of the study and an international expert on the condition who leads one of only a few specialty clinics on the syndrome in the nation.

“These findings suggest it may be helpful to keep an eye on patients with underlying health issues after COVID-19 vaccination to monitor for post-vaccine POTS,” said Chen, who also holds the Burns and Allen Chair in Cardiology Research at Cedars-Sinai.

The observational study, recently published in the peer-reviewed journal Heart Rhythm and presented during the American Heart Association Scientific Sessions, analyzed data from 10 patients treated at the Cedars-Sinai multidisciplinary POTS clinic between July 2021 and June 2022. When provided guideline-directed care, all study participants reported an improvement in their POTS condition.

Although there is an association between POTS and COVID-19 vaccination, a previous study of patient data across the Cedars-Sinai Health System found that patients diagnosed with COVID-19 were five times more likely to develop the cardiac condition after infection than after vaccination.

“COVID-19 infection itself seems to be either causing or unmasking a startling amount of POTS or POTS-like conditions globally,” said Debbie L. Teodorescu, MD, a cardiology fellow at the Smidt Heart Institute and first author of the study. “In our cohort, most patients responded well to treatment, but a subsequent COVID-19 infection tended to bring significant setbacks in recovery. That is why we urge all patients to be meticulous about avoiding COVID-19.”

Read more from the Cedars-Sinai Blog: Long COVID: What to Know

at Cedars-Sinai found that women who developed signs of elevated blood pressure during pregnancy were more likely to have residual evidence of abnormal heart structure and function up to a decade after the pregnancy.

“This study helps to clarify that, for some women, pregnancy is not just a ‘stress test’ that unmasks underlying cardiovascular risks,” said Susan Cheng, MD, MPH, the Erika J. Glazer Chair in Women’s Cardiovascular Health and Population Science, director of the Institute for Research on Healthy Aging in the Department of Cardiology in the Smidt Heart Institute, and senior author of the study. “This risk may also affect the heart years after pregnancy.”

The study, recently published in the peer-reviewed journal Hypertension, looked at more than 5,000 Hispanic/Latina women with at least one prior pregnancy and identified those who had hypertensive disorders of pregnancy, such as gestational hypertension, preeclampsia or eclampsia.

“This study confirms the results of others and demonstrates that women who experience a hypertensive disorder during their pregnancy are more likely to have lasting changes in the structure and function of their hearts than women who have normal blood pressure during their pregnancy,” said Natalie Bello, MD, MPH, director of Hypertension Research in the Smidt Heart Institute and co-author of the study. “Further, this work shows that only a portion of the abnormalities in the heart are explained by the woman’s current blood pressure.”

After accounting for other cardiovascular risk factors that might otherwise lead to early signs of heart disease, researchers found that the approximately 14% of study participants who had developed hypertensive disorders during pregnancy had several persistent heart-related issues found on cardiac imaging. These included greater heart-wall thickness, more frequent abnormal left-ventricle geometry and lower ejection fraction when compared to women who also had a prior pregnancy but without any related hypertensive disorder.

Although they make up a large and growing population of the United States, historically, Hispanic/Latina women have been underrepresented in medical studies. Using data from the Hispanic Community Health Study/Study of Latinos—a multicenter community-based study—investigators were able to engage this diverse population in their research. However, study authors say that given the underlying diversity of Hispanic/Latinx people, the findings of this study are not likely to be specific to any particular ethnicity, race or national origin.

“Cedars-Sinai has long invested in women’s heart health research, and this newest, critical study deepens our understanding of who is most at risk for hypertensive disorders in pregnancy,” said Christine M. Albert, MD, MPH, who is chair of the Department of Cardiology in the Smidt Heart Institute and holds the Lee and Harold Kapelovitz Distinguished Chair in Cardiology and was not involved in this study.

Read more from Cedars-Sinai Discoveries Magazine: Bridging the Data Gap on Hypertension During Pregnancy 

found that a monoclonal antibody treatment reduced the risk of COVID-19 in a large group of solid organ transplant patients who were administered the drug as a preventive measure against the disease.

The study, recently published in the peer-reviewed journal Transplant Infectious Disease, analyzed data from 911 solid organ transplant patients, 381 of whom had received at least one dose of the monoclonal antibody treatment tixagevimab−cilgavimab. The U.S. Food and Drug Administration (FDA) provided emergency-use authorization for the monoclonal antibody treatment in the fight against COVID-19 in immuno-compromised patients from December 2021 through January 2023.

“In this group of transplant patients, we found that the antibody reduced infection risk even amidst emergent Omicron subvariants,” said Stanley Jordan, MD, medical director of the Comprehensive Transplant Center’s Human Leukocyte Antigen and Transplant Immunology Laboratory and study author.

“Additionally, we concluded that pre-exposure monoclonal antibody therapy likely represents a therapeutic strategy that will continue to offer clinical benefit for immuno-compromised persons who are known to derive limited protection from vaccinations,” noted Jordan.

Solid organ transplant patients often receive antibody treatments designed to deplete T-cells and B-cells before their transplant, and they remain on long-term immuno-suppression after their procedure, as well, to reduce the risk of the body rejecting the new organ.

Because of this, transplant patients do not have a strong antibody response to COVID-19 vaccinations, making them particularly susceptible to contracting the disease due to lack of immunity. If infected with SARS-CoV-2—the virus that causes COVID-19—this patient population is often at the highest risk for severe, life-threatening disease.

“Our message is that these transplant patients are still at risk for severe outcomes, even if vaccinated,” said study author Susan Cheng, MD, MPH, the Erika J. Glazer Chair in Women’s Cardiovascular Health and Population Science and director of the Institute for Research on Healthy Aging in the Department of Cardiology in the Smidt Heart Institute at Cedars-Sinai. “We are hopeful that a replacement group of monoclonals will soon be approved by the FDA.”

To limit the risk of COVID-19 infection, study investigators recommend that solid organ transplant patients continue to wear masks in public places and avoid contact with individuals who are coughing or have had known contact with patients who have COVID-19.

Read more from the Cedars-Sinai Blog: COVID-19: What to Know About SARS-CoV-2 Reinfection

Their preclinical animal studies were published in two peer-reviewed journals: the Journal of Translational Medicine and Stem Cells Translational Medicine.

“The first study presents a path from laboratory discovery to patients,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and co-senior author of both studies. “And in the second, we showed that engineering the cells to release a powerful growth factor enhances their protective effect on retinal cells. This supports our previous studies where the same cells have shown promise as a therapy for neurodegenerative diseases,” said Svendsen, who also holds the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine at Cedars-Sinai.

In the study in Journal of Translational Medicine, investigators injected five different doses of neural progenitor cells—cells that give rise to various neural cell types—into the retinas of laboratory rats with retinal cell and vision loss similar to humans with retinitis pigmentosa. The condition causes the degeneration of the retina—the light sensitive layer at the back of the eye—resulting in vision loss and ultimately blindness.

The study showed that the animals’ ability to respond to light stimulation was significantly preserved six months after cell treatment, compared with untreated animals. In areas where the grafted cells were distributed, photoreceptor cells, which convert light into signals sent to the brain, were preserved. Part of the study’s purpose was to evaluate any risks related to the therapy, and the results suggested that the therapy could safely be used in clinical trials in human patients.

To determine the best method for delivering the cells in human clinical trials, investigators tested surgical methods for transplanting the cells into the retinas of laboratory minipigs, which have eyes of comparable size to the human eye. Ophthalmologist David Liao, MD, from the Retina-Vitreous Associates Medical Group in Beverly Hills, and Pablo Avalos, MD, associate director of Translational Medicine at Cedars-Sinai, performed the procedures and determined which automatic injection system yielded the best outcomes.

In the study published in Stem Cells Translational Medicine, investigators addressed disease stage.

“One reason results from other animal studies have not been replicated in clinical trials is that the studies were conducted in animal models at very early stages of disease,” said Shaomei Wang, MD, PhD, a professor of Biomedical Sciences and a research scientist in the Board of Governors Regenerative Medicine Institute at Cedars-Sinai as well as a co-senior author of both papers. “Human patients are generally recruited for clinical trials at much later stages of the disease, and it is important to test stem cell therapy at a disease stage that is relevant to these patients.”

To determine whether their therapies would be effective in late disease stages at which human patients would experience symptoms, investigators injected neural progenitor cells into the retinas of laboratory rats at later stages of retinal degeneration.

They also injected neural progenitor cells specifically engineered to express a protein called glial cell line-derived neurotrophic factor (GDNF). They found that cells both without or with the addition of GDNF offered dramatic retinal and vision preservation at both early and later disease stages.

However, GDNF-expressing cells provided better preservation, including broader protection of photoreceptor cells, than did treatment with only neural progenitor cells.

“Neural progenitor cells help preserve the structure of the retina, and the secreted GDNF offers direct photoreceptor protection,” Svendsen said. “Our next step will likely be a study to evaluate the safety of this therapy to eventually pave the way for clinical trials in humans.”

The Journal of Translational Medicine study was supported by California Institute for Regenerative Medicine grants LSP1-08235 and CIRM-EDUC2-08383, and funding from the Board of Governors Regenerative Medicine Institute at Cedars-Sinai.

The Stem Cells Translational Medicine study was supported by California Institute for Regenerative Medicine grants LSP1-08235, CIRM-EDUC-08383, CIRM-EDUC2-12638 and CIRM2-12638, and funding from the Board of Governors Regenerative Medicine Institute at Cedars-Sinai.

Read More on the Cedars-Sinai Blog: Regenerative Medicine—A New Path for ALS Treatment

“This is the best data to date on the question of surgery versus medical management in patients with this rare but serious condition,” said Adam Mamelak, MD, co-director of the Pituitary Center, director of the Functional Neurosurgery Program at Cedars-Sinai and lead author of the study. “It demonstrates in a prospective, controlled way what previous studies had begun to suggest, namely that pituitary apoplexy is very rarely a surgical emergency.”

The pituitary gland, located at the base of the brain, controls the function of several hormone-producing glands. Pituitary apoplexy occurs when a benign tumor in the pituitary gland area begins to bleed or dies, causing the tumor to grow and press on the surrounding brain tissues. This, in turn, causes symptoms such as severe headache, fatigue, confusion and vision problems that may include vision loss. Most commonly, these tumors are undetected prior to the apoplexy event.

To relieve the pressure on brain tissues and mitigate the symptoms of apoplexy, patients can either have the tumor surgically removed or be treated with medications to relieve pain and other symptoms while they wait for it to naturally shrink over time. In both cases, patients generally also need hormone-replacement therapy, Mamelak said.

Pituitary apoplexy has long been considered an emergency requiring rapid surgical treatment to achieve best results. Small retrospective studies, where investigators look back at previously collected data, have suggested that pituitary apoplexy patients have equally good outcomes with medical management, but these observations have failed to significantly change clinical practice.

“While we’ve seen a growing trend toward clinicians being a little more comfortable with medical management of pituitary apoplexy, in general, most patients still end up getting surgery,” Mamelak said. “Those small retrospective studies really didn’t move the needle that much.”

To provide a more solid basis for clinical decision-making, Mamelak and fellow investigators from the Department of Neurosurgery and the Pituitary Center at Cedars-Sinai—as well as colleagues from 11 other medical centers in North America, Japan, South Korea and Europe—developed the Pituitary Apoplexy Surgical Timing and Outcomes Registry (PASTOR).

The registry enrolled 97 patients with pituitary apoplexy at the time of diagnosis and compared outcomes for the 67 patients who had surgery with those for the 30 patients whose symptoms were medically managed. This type of prospective registry allows investigators to draw stronger conclusions because data collection is the same for all participants.

Investigators found that:

• Length of hospital stay was the same for patients who had surgery as for those who did not.
• Patients who had surgery experienced the same outcomes whether they had surgery right away or days after the onset of symptoms.
• There were no statistically significant differences in hormone function, vision or quality of life between the two groups of patients three and six months after treatment.

Mamelak noted that patients experiencing more severe vision symptoms were more likely to have surgery than those experiencing milder symptoms but that surgery didn’t necessarily lead to better outcomes.

“Cedars-Sinai and the other sites taking part in this study all have expert pituitary neurosurgery and endocrinology teams, which could help account for the positive outcomes experienced by surgical patients,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai. “A wealth of solid research tells us that outcomes from pituitary surgery are directly tied to surgical experience.”

Mamelak said that further research specifically looking at outcomes for people with visual field deficits would be needed to determine whether surgery is best in those cases. Meanwhile, the current findings could especially benefit medical centers that do not have the expertise to surgically treat pituitary tumors.

“These findings take some of the urgency out of managing these cases,” Mamelak said. “Clinicians at these centers now know that they can safely manage these patients medically and transfer them when it’s reasonable and available, or allow patients to forgo surgery entirely if they are comfortable with that.”

Read more on the Cedars-Sinai Blog: Neuroendoscopy Revolutionizes Skull Base Surgery

“We exposed mice to air similar to what we find near major Los Angeles freeways,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai, and senior author of the study. “We were surprised by the hundreds of genetic changes we saw in the brains of these mice. Many genes that interfere with learning and memory were turned on. And many genes necessary to maintaining structural support of the brain and maintaining cells that are critical for brain function were turned off.”

The study, which found that coarse airborne particles caused the most pronounced brain changes, could help government agencies prioritize targets for air quality regulation, Black said.

Half of the population has a genetic predisposition to Alzheimer's disease, according to Black. The progressive condition destroys memory and other mental functions, and genetic factors can increase a person’s risk of developing it as much as fivefold.

Previous research has shown a correlation between air pollution and Alzheimer’s disease in humans. And previous studies conducted at Cedars-Sinai found that exposing normal, healthy mice to polluted air caused inflammatory changes in the brain. This study built on that work, said Tao Sun, PhD, research scientist in the Department of Neurosurgery and the  co-senior author of the study.

“Our study covered a wider spectrum of sizes of particulate matter—from ultrafine to coarse—than previous studies did,” Sun said. “And the exposure time we used is significantly longer than in previously published research. It is the first study to show that this exposure accelerated some of the hallmarks of Alzheimer’s disease in genetically predisposed mice.”

Investigators exposed groups of laboratory mice with a genetic predisposition to Alzheimer’s disease to clean, filtered air and to air polluted with ultrafine, fine and coarse particulate matter for three and six months, then looked at the effects on their brains.

Because Alzheimer’s risk is based on a combination of genetic and environmental factors, the knowledge gained in studies such as this one can help improve health outcomes for patients, Black said.

“For people who have genetic risk factors, we will eventually be able to develop biomarkers and tests so that we can assess whether we need to take protective measures,” Black said. “This could help us prevent those individuals from exposure to a second or third impact, such as air pollution, that could accelerate development of Alzheimer’s disease.”

Going forward, the team will examine mice that were exposed to air pollution for a full year, since the exposure to air pollution in the real world is a chronic process. And Black said investigators will look into other factors, including infection and head injury, that could combine with genetic predisposition to accelerate the onset of Alzheimer’s disease.

Sun said investigators are also planning to look into the effects of air pollution on mice that represent a more common type of Alzheimer’s risk.

“In this study, we focused on so-called ‘familial’ Alzheimer’s disease with well-known inherited genetic factors, which accounts for a very small percentage of human Alzheimer’s patients,” Sun said. “In a future study, we plan to focus on the form most often found in humans. It is called sporadic or late-onset Alzheimer’s disease and involves genetic predisposition that is not inherited and is less understood.” 

Funding: This study was supported by Health Effects of Air Pollution Foundation grants number BTAP011, BTAP013 and HEAPF015.

Read more on the Cedars-Sinai Blog: Am I at Risk for Dementia? What You Need to Know

“These newly instated Research Town Halls are intended to create an ongoing dialogue between the research institute and investigators,” said Jeffrey Golden, MD, vice dean for Research and Graduate Education, director of the Burns and Allen Research Institute, and professor of Pathology and Laboratory Medicine at Cedars-Sinai. “Our hope is to create an open forum for faculty to express ideas and needs while also hearing firsthand about research opportunities, new developments and future planning at Cedars-Sinai.”

Golden shared several research-related updates, including an invitation to participate in Research Day, scheduled for Wednesday, March 27, 2024. The keynote lecture will be presented by David R. Liu, PhD, from the Broad Institute of the Massachusetts Institute of Technology and Harvard University.

Golden also detailed a newly established relationship with Tsinghua University in China. Recently, Cedars-Sinai welcomed five medical students from the university to work for two years—and possibly more—in various Cedars-Sinai laboratories. The next cohort of participants will be interviewed in 2024, and Golden expects to select another five to seven students from China to participate.

“In addition to hosting the inaugural five medical students, we are in the process of exploring opportunities for Cedars-Sinai faculty to spend short periods of time studying and training at Tsinghua University with a goal of establishing research collaborations,” Golden said.

Research Town Hall attendees also heard from Graciela Gonzalez-Hernandez, PhD, vice chair for research and education in the Department of Computational Biomedicine at Cedars-Sinai. Her topic—generative AI in healthcare—challenged listeners to dissect and question ChatGPT and other AI tools.

“ChatGPT is designed to please you by providing as many details as possible, but those details often lack context and sources,” Gonzalez-Hernandez said. “The field of artificial intelligence is now shifting toward a reinforcement learning to provide a measure of checks and balance.”

Reinforcement learning perceives and interprets a particular environment, takes suitable action, then learns through trial and error, Gonzalez-Hernandez said.

“Systems utilizing reinforcement learning can learn, grow and evolve—then be rewarded for making smart, solid decisions,” she said. 

Her presentation ended with a caution and a tip.  

The caution, which Golden underscored, is that the National Institutes of Health issued a statement prohibiting any form of ChatGPT from being used when reviewing grant applications. We all must be aware of the risk of using open-source software that will make confidential or protected information publicly available.

“My tip to you is that, instead of ChatGPT, I encourage the use of generative AI with greater transparency, like Perplexity.ai,” Gonzalez-Hernandez said. “This system acts as a next-generation search engine and displays the source of the information it provides.”

The final presentation by V. Krishnan Ramanujan, PhD, director of the Cedars-Sinai Biobank and a research associate professor of Medicine at the medical center, began with an announcement about some long-awaited news.

“We just learned that the Cedars-Sinai Biobank received accreditation from the College of American Pathologists,” Ramanujan said. “This accreditation recognizes our institutional biobank as a national center of quality that meets the highest standards.”

With the accreditation in hand, Ramanujan spotlighted the biobank’s team and vision.  

The Biobank and Research Pathology Resource Program comprises four service areas: biobanking, histology, research pathology, and microscopy and image analytics. Institutional partners include Enterprise Information Services, Anatomic Pathology, Facilities Operations, the Office of Research Compliance and Quality Improvement, and the Office of Research Administration.  

“Looking ahead, we will turn to the research community to take advantage of this state-of-the-art institutional resource and ask that we work together to develop new strategic collections,” Ramanujan shared. “Our team will continue advancing our tissue microarray resources, digital pathology workflows and biomarker validation platforms.”

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai.

The findings are published in the peer-reviewed journal Vaccines.

“The big message for primary care providers is that our words hold so much weight when it comes to helping patients make informed decisions,” said lead author Yelba Castellon-Lopez, MD, a primary care provider and a research scientist in the Department of Biomedical Sciences at Cedars-Sinai. “Taking a moment to ask ‘why’ can help you learn so much.”

In October 2021, the U.S. Food and Drug Administration authorized two COVID-19 vaccines for emergency use in children ages 5-11, but many eligible children remain unvaccinated.

In L.A. County, less than half of children ages 5-11 are vaccinated against COVID-19. These rates are even lower for Latin-American children in the area: Only 27.7% of these children had received at least one dose of a COVID-19 vaccine as of August 2023.

In March and April 2022, investigators conducted six virtual focus groups with 47 parents and caregivers of children ages 5-11. The parents and caregivers were recruited because of their participation in another study that assessed the effectiveness of MiVacunaLA, a mobile-phone text-based program meant to educate parents and caregivers and improve vaccination rates. Half of the parents and caregivers had been exposed to the intervention and half had not.

Answers from parents and caregivers fit into the following general themes:

• Needing to think about vaccinating their children more than about vaccinating themselves
• Needing trusted sources of vaccine information
• Being concerned about short- and long-term effects of the vaccine in children

Parents also said doctors and scientific studies are trusted sources of COVID-19 vaccine information and that they appreciate text messages containing information about COVID-19 vaccines. The investigators found that digital content, such as videos featuring doctors, can help parents in their decision-making.

The investigators are continuing to study how the MiVacunaLA program improves parents’ likelihood of vaccinating their children.

Funding: The study was funded by the VaxUp Innovation Challenge Grant sponsored by Children’s Hospital Los Angeles, the Los Angeles Department of Public Health and CEAL/STOP COVID-19 CA.

Read more on the Cedars-Sinai Blog: Tips to Navigate a COVID-19 Infection in Your Household

“This device has changed the lives of many of our tiniest patients and their families, who struggled with a very common but serious condition,” said Evan Zahn, MD, co-director of the Guerin Family Congenital Heart Program and director of the Division of Pediatric Cardiology at Cedars-Sinai Guerin Children’s and the Smidt Heart Institute. “It has meant fewer heart surgeries or medications that can cause dangerous side effects.”

Zahn was the first surgeon to implant the pea-sized mesh device, known as the Amplatzer Piccolo Occluder, to close a hole in the heart of a baby born with severe prematurity. The device was approved by the U.S. Food and Drug Administration in 2019.

Piccolo implantation is a minimally invasive approach designed to address patent ductus arteriosus (PDA), which is the most common heart defect seen in premature infants.

The ductus arteriosus is a blood vessel between the heart’s two major arteries that allows a fetus’ blood to bypass its lungs while it relies on its mother for oxygenated blood. Once a baby is born and needs to breathe on its own, the ductus arteriosus naturally closes. If it doesn’t, it can cause extra blood to flow into the baby’s pulmonary arteries and can contribute to severe lung disease, bleeding in the brain, problems with the bowels and even death.

Medication therapy for PDA can cause side effects, such as kidney failure and bleeding, and heart surgery to close the PDA can lead to long-term health issues. 

To implant the Amplatzer Piccolo Occluder, a physician guides a catheter through a vein in the leg to the heart and closes the hole. The procedure takes a few minutes.

For this study, investigators looked into PDA-related health outcomes in 200 premature babies who were enrolled in the Piccolo clinical trial between June 2017 and February 2019. Nine children enrolled in the study died, but the deaths were determined to be unrelated to the device or procedure.

Imaging showed full PDA closure in the 33 patients for whom this data was available three years after they had the Piccolo device implanted.

Zahn and his team have since developed a technique to perform the procedure at the bedside, rather than in the catheterization laboratory, as was done during this clinical trial.

According to the study authors, “This offers the benefit of allowing experienced practitioners to continue to care for these patients in the units that know them best without the need for transport.”

Funding: The study was funded by Abbott Structural Heart, the company that makes the Amplatzer Piccolo Occluder.

Conflicts of interest: Several study authors reported conflicts of interest. Brian H. Morray is a consultant and proctor for Abbott Structural Heart. Shyam K. Sathanandam: proctor/consultant for Abbott. Thomas Forbes: proctor/consultant for Abbott, Edwards, AcuNav/Biosence Webster, B. Braun Medical, Siemens, Medtronic. Matthew Gillespie: proctor/consultant for Abbott, Medtronic, W.L. Gore & Assoc. Darren Berman: proctor/consultant for Abbott, Edwards, Medtronic. Aimee K. Armstrong: proctor/consultant for Abbott, Edwards, Medtronic, Cook Medical. S. Shahanavaz: proctor for Abbott, Medtronic, Edwards. Thomas Jones: research grant; proctor/consultant for Abbott, Edwards, Medtronic, W.L. Gore & Assoc.. Toby Rockefeller: proctor for Abbott. Henri Justino: proctor/consultant for Abbott, Baylis Medtech, Chiesi USA, Edwards Lifesciences, Medtronic; Clinical Trial Executive Committee for Janssen Pharmaceutical; co-founder of PolyVascular; scientific advisory board for Pediastent. David Nykanen: proctor for Abbott; consultant and independent data reviewer for W.L. Gore & Assoc.; expert witness for Glaxo Smith Kline. Courtney Weiler: full-time employee at Abbott. Dan Gutfinger: full-time employee at Abbott. Evan M. Zahn: consultant/proctor for Abbott, Edwards, Medtronic, National PI ADO II AS IDE Trial and Alterra/S3.

Read more on the Cedars-Sinai Blog: Making Strides in Treating the Smallest Heart Patients

Nearly 215 in-house and visiting postdoc researchers from across the country and around the world who are conducting research and receiving and providing training at Cedars-Sinai participated in a week of special events designed to foster networking and collaboration.

Activities included dedicated social time, an elevator pitch contest, a scientific art contest, a treasure hunt, and a career panel comprising professionals with PhDs from diverse backgrounds and industries. Unlike last year’s mostly virtual events, this year the events were in-person with the option to attend virtually.

“The biggest benefit of the week is the opportunity to network within our Cedars-Sinai postdoc community,” said Sarah McCallum, PhD, a postdoctoral scientist in the Burda Laboratory at Cedars-Sinai and a member of the Cedars-Sinai Postdoc Society Leadership Committee, which plans the week’s activities.

“We often underestimate the importance of conversation with colleagues that happen away from the bench—for example, just by getting coffee together—and that spark collaborations and new ideas, help us overcome technical issues or even help us get that next grant or job,” McCallum explained.

Florian Rosier, PhD, a postdoctoral scientist in the Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai and a member of the Cedars-Sinai Postdoc Society, said, “It’s nice to be a part of this community and to meet each other at different events, since we’re coming from all over the world as well as working on different parts of campus.”

Postdoctoral scientist Monica Wagner, PhD, attended the career panel, which included speakers from industry, academia, government and biotech startups, and said she enjoyed learning more about the career possibilities within the scientific community—including those not previously on her radar.

“It was a very informative panel,” Wagner said. “The passion and dedication of the panelists left me with a deeper appreciation for the various career paths within the scientific field. Also enlightening was hearing more about the similarities and differences in the goals and objectives of academia and industry.”

Paul Linesch, PhD, a postdoctoral scientist in the Breunig Laboratory at Cedars-Sinai, won the event’s elevator pitch contest. He summarized his research—studying how stem cells turn into different types of cells in the brain—in less than a minute while making it easy to understand for all audiences.

Linesch also took third place in the art contest with “Folding the Mind,” his photograph of the cerebellum of a mouse brain.

“We are a neurodevelopment lab, and we’ve been collaborating with another professor investigating a gene involved in the development of the cerebellum,” Linesch said. “The cerebellum is a beautiful structure, and this photo is one of my favorites.”

Vladimir Zhemkov, PhD, won first place in the art contest with “The Garden of Life,” which depicts spinal motor neurons growing on a microfluidic chip. Jyoti Chhimwal, PhD, won second place with the image “Mitotic Supernova,” depicting the beginning of life at the cellular level.

Other winners in the elevator pitch contest were Umer Farooqi, PhD, in second place, and Reyhaneh Jamali Khoshschehreh, PhD, in third place.

A treasure hunt also was among the week’s activities. Postdocs set out across the Cedars-Sinai campus to find and photograph various items—including selfies with each other. Winners of the treasure hunt were Taylon Silva, PhD, in first place; Umer Farooqi, PhD, in second place; and Elisabeth Jaeger, PhD, in third place.

National Postdoc Appreciation Week is recognized at academic institutions nationwide. At Cedars-Sinai, events are planned by the Postdoctoral Scientist Program and Cedars-Sinai Postdoc Society as a way to celebrate the year-round accomplishments and contributions of postdoctoral investigators and foster networking among junior researchers and the local research community.

The Cedars-Sinai Postdoc Society hosts a regular hybrid meeting at 3 p.m. on the second Monday of every month featuring a scientific and educational seminar as well as a bi-monthly coffee hour for postdocs to network. To volunteer, give a seminar, or contact the Postdoc Society, email GroupPostdocSocietyCommittee@cshs.org.

The Cedars-Sinai Postdoc Society’s committee members are Florian Rosier, PhD; Sheryl Fernandes, PhD; Esther Adeniran, PhD; Adiza Abass, PhD; Rasaq Akinsola, PhD; and Sankalp Tikoo, PhD; in addition to co-chairs Sarah McCallum, PhD; Saeed Seyedmohammad, PhD; and Elisabeth Jaeger, PhD.

The study, published in the Journal of Pain, compared patient education and clinical decision support for managing opioids. A simple patient education intervention improved overall satisfaction with patient communications, while a carefully crafted electronic alert showed greater potential to reduce high-dose opioid prescribing. No difference was found in pain interference between the two groups.

“The goal of our study was to help patients and doctors make safer decisions when prescribing opioids for chronic pain while also seeking to avoid the stigma sometimes attributed to using pain medications,” said Brennan Spiegel, MD, MSHS director of Health Services Research, George and Dorothy Gourrich Chair in Digital Health Ethics, and the study’s lead author. “We want to make sure we’re maximizing the appropriateness of dosing so we’re helping people manage their pain without doing harm.”

The study was funded by a Patient-Centered Outcomes Research Institute grant. One in 5 American adults experience chronic pain. Overdose deaths In the U.S. related to prescription opioids increased by over 4 times compared to 20 years, according to the National Institutes of Health, constituting a public health crisis.

“Patients and their physicians both struggle to manage chronic pain, particularly when opioids become involved,” said Itai Danovitch, MD, chair of the Department of Psychiatry and Behavioral Neurosciences. “We now understand that opioids are double-edged swords—when it comes to chronic pain, their harms are often greater than their benefits. Our study showed that both clinical decision support and patient education can have positive effects. We need continued support to help physicians adopt best practices, and we need effective education to empower patients to promote their own health.” 

Investigators compared the effectiveness of physician-directed clinical decision support administered through the electronic health record versus patient-directed education to promote the appropriate use of opioids through a cluster-randomized trial. 

The trial included 82 primary care physicians at Cedars-Sinai and 951 of their patients with chronic pain. They measured outcomes based on satisfaction with patient-physician communication, patient interference, physical function, depression, high-risk opioid prescribing, and co-prescribing of opioids and benzodiazepines.

The outcomes were the same in both groups on most measures, but patient education was linked to higher satisfaction with communications and the electronic alerts with lower opioid dosing.

Dodging Alert Fatigue

Cedars-Sinai has been on the forefront of using clinical decision support, Spiegel said. Too many alerts, however, can lead to them being ignored.

The alert in this study was a point-of-care reminder that would pop up on the computer screen to help identify if opioids were being prescribed but might not be the most appropriate intervention. 

“We worked very closely with our colleagues in primary care in the Medical Delivery Network to make sure the alert was appropriate,” Spiegel said. “We wanted them to have a direct role in crafting it and vetting it, which isn’t always the case with the alerts doctors routinely experience in the electronic health record.” 

In addition, to avoid alert fatigue, the alerts had clear action items rather than simply providing additional information. For example, the medical network runs and opioid withdrawal program, and the alerts had a button to refer patients to the program if appropriate.

As many as 85% of alerts are simply dismissed by clinicians, said Teryl Nuckols, MD, MSHS, director of the Division of Internal Medicine.

“That these alerts can be effective in reducing the rate of high dose opioids is a powerful finding,” she said. “It’s not easy to change clinician behavior, and the engagement work that was done seems to have made a significant difference.”

Scalable Interventions

The other arm of the study provided ready-made materials to patients, arming them with questions to ask should opioids be prescribed to them and informing them of the risks.

The study team also included a chronic pain patient who created a newsletter that was sent out to patient participants each month, providing updates about the research and information about the team. In addition, the research team formed a patient advisory panel who met quarterly to advise on all aspects of the study.

Ultimately, the study concluded that patient educational materials is an inexpensive, easily scaled intervention that can improve satisfaction with patient-provider communications. Clinical decision support is a more resource-intensive undertaking, but provided benefits that education alone could not. Using the combination in primary care warrants further study, Spiegel said.

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai.

at Cedars-Sinai have found that community-level socioeconomic disparities are associated with worse three-year survival rates for patients with degenerative mitral regurgitation who had valve repair surgery.

The findings, recently published in the Journal of Thoracic and Cardiovascular Surgery, showed that patients from socioeconomically distressed communities had an approximate 20% increased risk of three-year mortality after their mitral valve repair, and an almost 30% increased risk of heart failure readmission.

Previous studies had demonstrated mixed results regarding racial disparities in mitral valve repair rates and short-term outcomes, and little was known about the midterm impact of socioeconomic distress on repair outcomes.

“Our findings add to the growing body of literature highlighting that racial and socioeconomic disparities exist in cardiovascular health and in cardiac surgical outcomes and that they impact overall long-term care,” said Jad Malas, MD, a  cardiothoracic surgery resident in the Smidt Heart Institute and lead author of the study. “Even when narrowing our research to focus on a very specific population of patients undergoing a very specific surgery, disparities still exist.”  

To conduct the study, investigators used data from the Centers for Medicare and Medicaid Services to identify 10,322 patients who were undergoing first-time isolated surgical repair for degenerative mitral regurgitation between 2012 and 2019.

They used the Distressed Communities Index, which has previously predicted poor cardiac surgical outcomes, to classify distressed patients. The Distressed Communities Index incorporates education level, poverty, unemployment, housing security, median income and business growth.

Of the 10,322 patients, 1,003 (9.7%) came from distressed communities and were more often female (55.3% from distressed communities vs. 50.5% from nondistressed communities) and Black (11.6% vs. 2.7%). Additionally, they had mitral valve surgery at lower-volume centers (11 cases per year vs. 16 cases per year) and traveled farther for surgery (40 miles vs. 17 miles).

Post-repair survival rates at three years in patients from socioeconomically distressed communities and nondistressed communities was 85.4% and 89.7%, respectively.

Investigators noted that potential ways to address this disparity could include improving access to high-volume centers and earlier referral for mitral valve surgery, before the disease worsens. But, they added that access to high-volume centers alone would likely not be sufficient to resolve the disparity in midterm outcomes, which is influenced by other factors.

“Ultimately, this study demonstrates that socioeconomic status matters,” said senior and corresponding author Michael Bowdish, MD, vice chair of the Department of Cardiac Surgery. “It is important that we continue to recognize that inequities exist among patients undergoing mitral valve repair, and we hope that by understanding these disparities, we can better support these patients and ensure they continue on the right path after surgery.”

Mitral valve regurgitation affects more than 2 million Americans. Historically, heart surgeons corrected a faulty mitral valve by replacing it with an artificial one via open-heart surgery. Today, specialists are able to repair, rather than replace, the valve through minimally invasive surgery. It is low risk and successful in nearly 100% of patients having degenerative mitral valve repair in the United States.

Since 2017, the Smidt Heart Institute has received the highest national ratings for mitral valve surgery from the Society of Thoracic Surgeons, and it was recently designated a Mitral Valve Repair Reference Center by the Mitral Foundation. The institute is highly regarded for its record of superior clinical outcomes resulting from evidence-based, guideline-directed degenerative mitral valve repair.

Study author Joanna Chikwe, MD, chair of the Department of Cardiac Surgery at Cedars-Sinai, noted that the Smidt Heart Institute’s health outcomes research program is working to better understand disparities and how they impact the field and society at large.  

“The findings from the mitral outcomes study are a call to action to consider how we effectively care for patients,” said Chikwe, who also holds the Irina and George Schaeffer Distinguished Chair in Cardiac Surgery. 

“As physicians, we can work to better understand our patients—their background, where they live, the support they have at home. We can remind them about the importance of getting an echocardiogram every year and encourage follow-up visits after surgery. We need to identify factors that can help our patients have better outcomes in the long term.” 

Other Cedars-Sinai investigators involved in the study include Qiudong Chen, MD; Dominic Emerson, MD; George Gill, MD; Georgina Rowe, MD; and Alfredo Trento, MD.

Funding: The study was funded by the National Institutes of Health for advanced heart disease research (award number T32HL116273).

Read more from the Cedars-Sinai Blog: Heart Disease: When to Get a Second Opinion

The results of the representative study are published in the journal Gastroenterology.

“This new study is among the largest population-based evaluations of IBS epidemiology. The results reveal that the condition is more prevalent than previously thought and varies by race and ethnicity,” said the study’s corresponding author, Brennan Spiegel, MD, MSHS, director of Health Services Research and the Dorothy and George Gourrich Chair in Digital Health Ethics at Cedars-Sinai.

In May and June of 2020, investigators conducted online surveys of adults age 18 and older. A large cross section of people living in the U.S. were asked to complete the Rome IV IBS questionnaire and the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) survey to assess the presence and severity of their gastrointestinal symptoms.

“We wanted to update our understanding of how common IBS is in the U.S. and to get a sense of the associated burden of the illness. Because diagnosis is symptom-based, we used the Rome IV validated IBS questionnaire to survey respondents about their abdominal pain and changes in bowel habits. We also used the PROMIS survey to see what other symptoms they were experiencing,” said gastroenterologist and co-first author of the study Christopher Almario, MD, MSHPM, who is also an assistant professor of Medicine at Cedars-Sinai.

In addition to the significant size of the study cohort, investigators point out there have been few large-scale studies looking at racial and ethnic differences in IBS.

“Our findings showed that non-Hispanic Black people, Hispanics and non-Hispanic Asian people all were less likely to have IBS when compared to non-Hispanic white people,” said Almario.

“But some of the non-white participants who did have IBS experienced more severe symptoms. For example, Hispanics and non-Hispanic Black people with a form of IBS where diarrhea is common had more severe belly pain than their non-Hispanic white counterparts,” said Almario.

Since the prevalence of IBS appears to be on the rise, Almario suggests physicians may be seeing more patients with associated symptoms in their clinics.

“In addition to abdominal pain and changes in bowel habits, patients with IBS may experience bloating, excess gas and heartburn. It is important for healthcare providers to take a thorough patient history in order to identify and manage these treatable symptoms,” said Almario.

According to the study authors, the COVID-19 pandemic may have played a role in the increased prevalence of IBS, and they are performing additional data analysis to examine the potential connection.

“It is possible that both direct infection with the virus that causes COVID-19 and the psychological stress associated with living through a pandemic contributed to the rise in IBS prevalence through a number of mechanisms worthy of further investigation,” said Spiegel.

DOI: https://doi.org/10.1053/j.gastro.2023.08.010

Funding: Support for this study was provided by Ironwood Pharmaceuticals in the form of an institutional research grant to Cedars-Sinai.

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai.

Read more on the Cedars-Sinai Blog: When to See a Doctor for Constipation

concluded that the reformulated version is less toxic to the heart than the version in wide use since the 1960s.

“Our lab tested this new version of doxorubicin on heart cells that we created from induced pluripotent stem cells—skin or blood cells that have been sent back in time to become stem cells that we can then use to generate any cell type in the human body,” said Arun Sharma, PhD, research scientist in the Board of Governors Regenerative Medicine Institute, the Smidt Heart Institute, Cedars-Sinai Cancer and the Department of Biomedical Sciences at Cedars-Sinai, and co-senior author of the study. “We found that this reformulation is much less toxic to the heart than the original version of the drug, and that could be good news for many cancer patients.”

Early-phase clinical trials of the new formulation have received a green light from the Food and Drug Administration and will soon be underway, Sharma said.

Doxorubicin is a common chemotherapy drug and used to treat breast, bladder and several other cancers, but can cause serious heart damage. To help protect the heart while preserving the drug’s cancer-killing benefits, Xiaojiang Cui, PhD, professor of Surgery at Cedars-Sinai, researcher at Cedars-Sinai Cancer and co-senior author of the study, encapsulated the drug in a protein called albumin.

“Albumin is one of the most common proteins found in the bloodstream, and tumor cells take up a lot of albumin as a nutrient,” Cui said. “We hypothesized that by encapsulating doxorubicin in albumin, more of the drug would be rapidly taken up by tumor cells and less would make its way to the heart.”

Tests of this new version of the drug—called single-protein encapsulated doxorubicin, or SPEDOX-6—showed that human cancer cells robustly took in the encapsulated medication and that it killed the cells efficiently.

Sharma and his team then tested the heart safety of the new formulation.

The team first exposed different cell types within the heart, generated in a dish from stem cells, to traditional doxorubicin and SPEDOX-6, and found that SPEDOX-6 killed fewer of the cells. They also found that human stem cell-derived cardiomyocytes—heart muscle cells that beat even in the laboratory dish—kept beating if exposed to SPEDOX-6 but lost function if exposed to traditional doxorubicin.

SPEDOX-6 also proved less heart toxic when tested on a new laboratory model called 3D cardiac spheroids, previously developed by the Sharma Lab.

“These are 3D spheres made up of fewer than 100,000 heart muscle cells, heart blood vessel cells and other cell types found in the heart,” Sharma said. “They are all grown from stem cells. You can barely see the spheres with the naked eye, but they allow us to rapidly and accurately test the heart toxicity of various substances.”

The team also created stem cell-derived heart cell models from individual cancer patients who had experienced heart damage from doxorubicin treatment—indicating that their hearts were especially vulnerable to the effects of the drug. Again, SPEDOX-6 caused significantly less damage to the cells than the original doxorubicin formulation did.

Going forward, the teams plan to encapsulate other chemotherapy drugs in albumin in the hope of improving both their cancer-killing efficiency and their safety for the heart.

“Widespread use of doxorubicin and other cardiotoxic chemotherapies demonstrates the urgent need to identify effective anti-cancer treatments that are safer for the heart,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai. “These human stem cell-derived models offer a path to identify such treatments and, because of the ability to create patient-specific testing models, also could provide future developments in precision medicine for both cardiology and oncology.”

Other Cedars-Sinai co-authors of this study include first authors Madelyn Arzt and Bowen Gao, as well as Maedeh Mozneb, Stephany Pohlman, Qizhi Liu, Yi Zhang, Xuemo Fan, Amelia Jenkins and Armando Giuliano.

Funding: The study was funded by American Heart Association Career Development Award number 856987; National Institutes of Health grant number 2R01CA151610; Department of Defense grant number W81XWH-18-1-0067; the Uretsky BRCA Research Fund; the Samuel Oschin Comprehensive Cancer Institute Research Development Fund; the Cedars-Sinai Cancer Center; the Fashion Footwear Charitable Foundation of New York, Inc.; the Margie and Robert E. Petersen Foundation; the Linda and Jim Lippman Fund; the Board of Governors Regenerative Medicine Institute at Cedars-Sinai; a NASA In-Space Production Award; the Donna and Jesse Garber Award for Cancer Research; and a California Institute for Regenerative Medicine Bridges Award.

Read more on the Cedars-Sinai Blog: What Are Induced Pluripotent Stem Cells?

concluded that further research is needed to clarify the reasons for this disparity.

“We’ve known for years that Black women with endometrial cancer have lower survival rates than white women, largely because they are more likely to have an aggressive subtype and to be diagnosed at an advanced stage,” said Kristin Taylor, MD, assistant professor of Obstetrics and Gynecology at Cedars-Sinai and lead author of the study. “But our study found this disparity persists even when we compare patients with the lowest-risk form diagnosed at the earliest possible stage.”

Taylor and fellow investigators reviewed data on more than 23,000 Black and white women from the National Cancer Institute’s SEER database, which collects data from registries in 18 geographic areas in the U.S. All of the patients had the earliest-stage, least-aggressive endometrial cancer—a type called stage 1A low-grade endometrioid endometrial carcinoma.

“Low-grade endometrioid tumors account for about 80% of endometrial cancers, and most of these are stage 1 at diagnosis,” said Taylor. “For these patients, standard treatment is hysterectomy, and many should be cured without the need for radiation or chemotherapy.”

The SEER data showed that the vast majority of patients, both Black and white, were treated with hysterectomy and had high overall survival rates. However, while just 1% of white women did not receive hysterectomies, 3% of Black women in the study didn’t receive this lifesaving surgery.

“We had hoped that when we looked only at the lowest-risk patients, the disparity between Black and white women would disappear, but it did not,” Taylor said. “It’s disappointing.”

Residing in the South, being insured with Medicaid, and residing in a county with low median income were also associated with not receiving surgery.

Study investigators said doctors might recommend against hysterectomy for women—both Black and white—with underlying health conditions that increase risk of surgical complications. Doctors might also offer women of childbearing age a fertility-sparing hormone treatment that lets them temporarily postpone surgery, Taylor said.

However, a slightly higher—though not statistically significant—number of Black women than white women refused surgery when their doctors recommended it, the study found.

“Although there was no data collected on the reason for refusal,” Taylor said, “there is likely an element of mistrust of the medical community that contributes to this difference.”

One factor that might help account for this disparity is structural racism, Taylor said. She pointed to historical policies that caused more Black people to be of lower socioeconomic status, and thus more likely to be uninsured or underinsured and have less access to quality healthcare. She also noted prior medical experimentation on Black people (e.g., the Tuskegee syphilis study) as recently as a few decades ago.

“Even though they might not always be in our conscious memory, I think that the downstream effects of those insults from decades ago get passed on culturally, particularly in the South. Among my own family, I see geographical differences in how members perceive their relationships with their doctors,” said Taylor, who was born in the South but grew up in Illinois.

Taylor said that further studies should be conducted to delve into the roles of these social factors.

“Disparities in survival that persist even among patients with the same stage and subtype of cancer must be investigated and addressed,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE One Distinguished Chair. “Dr. Taylor’s work is an example of the many ways investigators at Cedars-Sinai Cancer are working to understand these disparities and bring the highest level of care to all of the diverse patient groups we serve.”

Going forward, Taylor and team plan to address some limitations of the current study by looking at a different dataset.

“One major limitation with the SEER database is that socioeconomic factors are recorded at the county level, which is so broad,” Taylor said. “We're essentially repeating this study using the California Cancer Registry, which gives information including median income, education level, insurance status, primary language and immigration status at the neighborhood level. We'll have a much richer, more granular view of the lives of these patients, which should be really informative.”

Another planned study goes in a completely different direction.

“Some data suggest that there are different genetic pathways, even within this narrow subset of tumors, that could be driving disparities between outcomes in Black and white women,” Taylor said. “We’re hoping to develop models in the lab derived from the tumors of Black and white women with this subtype of cancer to look for biologic differences that could help inform treatments for each population.”

Read more on the Cedars-Sinai Blog: Uterine Cancer: What Women Need to Know

A recent study published in Frontiers in Immunology offers broader insight into the protein networks that allow immune cells to respond to harmful substances. This discovery could lead to treatments that leverage the body’s natural healing processes.

“This study demonstrates enormous potential for exploiting the natural immune process to better fight disease,” said Maya Koronyo-Hamaoui, PhD, a professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “White blood cells—which we studied here in the context of Alzheimer’s disease—are one of the first lines of defense against a variety of foreign and internal threats and are key for regulating tissue repair and maintenance.”

The study demonstrates the significance of osteopontin (OPN), a protein expressed by macrophages, a type of white blood cell that surrounds and destroys harmful organisms and clears cell debris and the buildup of abnormal proteins. Investigators, in collaboration with the Van Eyk Research Lab at Cedars-Sinai, concluded that OPN deficiency disrupts the balance of proteins in macrophages, eventually causing them to die.

“Macrophages clear toxic proteins, reduce inflammation, and help regenerate, rejuvenate, and encourage newly formed connections in the brain,” said Koronyo-Hamaoui.

The study builds on two previous studies from the Koronyo-Hamaoui Llab—published in Brain Behavior and Immunity and Brain—detailing the critical role played by bone-marrow derived macrophages and OPN expressed in macrophages in clearing Alzheimer’s disease-related amyloid-beta peptides and supporting central nervous system repair and regeneration.

“Our work supports further study into gene editing or immunotherapies that could have multifaceted impact,” said Altan Rentsendorj, PhD, a senior research associate in the Koronyo-Hamaoui Lab and first author of the study.

Investigators studied macrophages in laboratory mice. They compared normal cells, diseased cells treated with an FDA-approved multiple sclerosis treatment that caused them to overexpress OPN, and cells without the ability to produce OPN.

They found that diseased macrophages treated with the multiple sclerosis medication more effectively cleared amyloid-beta proteins and increased their anti-inflammatory activity. However, in cells without the ability to produce OPN, treatment with the multiple sclerosis medication did not restore normal protein expression.

Investigators also discovered that the presence of OPN is necessary to produce two other crucial anti-inflammatory molecules. Dysfunction of the first, ubiquitin C-terminal hydrolase L1, has been implicated in neurodegenerative diseases such as Alzheimer’s. The second, heme oxygenase 1, plays a critical role in preventing vascular inflammation.

“We were surprised to find that other neuroprotective proteins are dependent on OPN,” Rentsendorj said. “This work shows that OPN is critical for the machinery of rejuvenation in these innate immune cells.”

The Koronyo-Hamaoui Lab also recently published a review paper in Frontiers in Physiology synthesizing knowledge about angiotensin converting enzyme (ACE) and its role in Alzheimer’s disease. ACE, expressed by immune cells, degrades amyloid-beta and improves immune response.

The review outlines findings from 1975 onward, including numerous studies from the Koronyo-Hamaoui Lab in collaboration with the Bernstein Lab at Cedars-Sinai.

Significant among these are a 2020 paper published in Brain, which demonstrated that overexpression of ACE enhances the ability of white blood cells called monocytes to rid the body of toxic forms of amyloid-beta oligomers and fibrils, and a 2014 paper published in The Journal of Clinical Investigation. The review also notes that an analysis of human genome sequencing found people with a genetic variant that leads to lower expression of ACE in their blood had higher risk for Alzheimer's disease.

“This review builds a strong case for targeting monocytes and ACE in Alzheimer's disease,” said neurology fellow Ron Danziger, MD, first author of the review paper. “In extensive studies by the Koronyo-Hamaoui and Bernstein labs, we have consistently found an amazing effect of ACE on the characteristics of macrophages in the context of Alzheimer’s disease.”

Taken together, the new papers support the need for further research into therapies that might leverage immune function in blood or bone marrow cells to fight neurodegenerative disease.

“We need a much more effective treatment to address many aspects of Alzheimer’s disease,” said Keith L. Black, MD, chair of the Department of Neurosurgery, the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai, and co-author of both studies. “Genetically manipulating monocytes to enhance ACE or OPN, which would target more than plaque clearance, could be a very promising technique.”

Funding: The study appearing in Frontiers in Immunology was funded by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG056478, R01AG055865, AG056478-04S1 and R01AG075998) and the Tom Gordon, Haim Saban and Wilstein foundations.

The study appearing in Frontiers in Physiology was supported by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG055865, R01AG056478, R01AG075998 and R01AG042195); a BrightFocus Foundation Award; The Coins for Alzheimer’s Research Trust (CART) Fund; the Cedars-Sinai Jona Goldrich Center for Alzheimer’s and Memory Disorders; the Saban, Gordon, Marciano and Wilstein private foundations; and the National Center for Advancing Translational Sciences (CTSI grant UL1TR000124).

Read more from the Cedars-Sinai Blog: How to Help a Loved One With Alzheimer’s or Dementia

In this study, the investigators explored combining standard immune checkpoint inhibitors with a new class of immunotherapies called ImmTACs (immune-mobilizing monoclonal T-cell receptors against cancer).

While immune checkpoint inhibitors prevent tumors from deactivating cancer-killing immune cells called T-cells, ImmTACs draw T-cells directly to tumor cells via receptors for T-cells on one side and tumor cells on the other.

“The results of this study point toward new combination treatments that can help patients whose melanoma has progressed despite first-line therapy,” said Omid Hamid, MD, chief of Translational Research and Immuno-Oncology at Cedars-Sinai Cancer at The Angeles Clinic and Research Institute, medical director of the Cutaneous Malignancies Disease Research Group at Cedars-Sinai Cancer, and lead author of the study. “Once these treatments receive regulatory approval, they represent the next set of options for these skin cancer patients.”

The study enrolled 85 patients whose malignant melanomas had progressed despite previous treatment with standard immune checkpoint inhibitor therapy. All were treated with a combination of an ImmTAC and immune checkpoint inhibitors. The combination produced one-year overall survival rates above 76%, with no unexpected side effects.

The ImmTAC used in the study, tebentafusp, is the first drug to be approved by the U.S Food and Drug Administration (FDA) for treating ocular melanoma, the most common type of eye cancer.

While cutaneous melanoma—cancer that forms in the skin’s pigment-producing cells—isn’t the most common form of skin cancer, it is the most lethal, Hamid said. It causes about 10,000 deaths in the U.S. each year by spreading deeper into the skin or to other parts of the body.

Immune checkpoint inhibitors have dramatically improved survival rates for patients whose skin cancer has spread. Many of these drugs—including pembrolizumab, nivolumab, avelumab, ipilimumab, durvalumab and atezolizumab—have been studied by Hamid and his team in first-in-human clinical trials to treat melanoma. Later, the therapies also were approved by the FDA to treat basal and squamous skin cancers, as well as lung, gastroesophageal, endometrial and breast cancers.

“A decade or so ago, median survival for metastatic melanoma was six months,” Hamid said. “But thanks to our ability to harness the power of the immune system, the median survival is now six years and greater. Unfortunately, these immune checkpoint inhibitors don’t work for everyone.”

Previous studies have shown that immune checkpoint inhibitors like nivolumab and pembrolizumab benefit only 30%-40% of patients.

“Adding an ImmTAC to these immune checkpoint inhibitors produced an amazing one-year survival rate,” Hamid said. “This was also the first trial to show that we can safely combine ImmTACs and immune checkpoint inhibitors in patients whose cancer progressed despite treatment with standard immune checkpoint inhibitor therapy.”

This data has now been translated to other clinical trials with ImmTACs that offer options for patients with a wide variety of tumors, including melanomas, sarcomas, and endometrial, ovarian, and non-small cell lung cancers, Hamid said.

Investigators are moving forward with a Phase III trial of the tebentafusp and immune checkpoint inhibitor combination for patients with newly diagnosed cutaneous melanoma.

“The incidence of cutaneous melanoma is increasing dramatically,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “Metastatic disease is difficult to treat, but through innovations and trials, we have made major strides in extending survival for these patients. We are continually exploring cutting-edge therapies to provide new opportunities for these patients.”

Funding: The study was funded by pharmaceutical developer Immunocore Ltd.

Read More on the Cedars-Sinai Blog: Don’t delay getting a skin exam. Here’s what to expect

In a new study published in the journal IBD, investigators used a novel statistical approach to identify three new regions of the genome associated with developing IBD. They also discovered other areas that were specifically associated with developing IBD in only one sex.

“We observed sex differences in the prevalence of specific clinical characteristics. Females were more likely to have Crohn’s disease affecting only the colon. In males, on the other hand, we saw a higher risk for perianal complications in Crohn’s disease as well as more extensive disease in ulcerative colitis,” said Talin Haritunians, PhD, the senior author of the study and a research associate professor of Medicine at Cedars-Sinai.

Haritunians, a research scientist in the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, noted the study was the first international investigation into sex-stratified genetic associations in IBD containing more than 70,000 subjects.

“Most genetic association studies analyze males and females together. Our study highlighted the need to move beyond the conventional sex-combined analyses in order to fully appreciate the complex genetic architecture of IBD,” said Dermot McGovern, MD, PhD, a co-author of the study and director of Translational Research in the Inflammatory Bowel and Immunobiology Research Institute.

The sex-dimorphic analytic approach used by the investigators identified associations in three new genetic loci (chr9q22, CARMIL1 and UBASH3A) as well as distinct sex-specific patterns of association for several variants, including on chromosome-2 and in the major histocompatibility complex on chromosome-6.

“This is of particular interest given the well-established role of the major histocompatibility complex and HLA locus in IBD and immune-mediated diseases, in general,” said Haritunians.

The investigators say they are continuing the collaboration with the IBD international consortium and are currently expanding the study to include a cohort of more than 100,000 people.

“We plan to also develop sex-specific IBD genetic risk scores to better evaluate the genetic ‘burden’ in males and females,” said Haritunians.

This novel approach to genetic research of sex differences in IBD will also be used in Cedars-Sinai’s large-scale studies of the disease in Black and Hispanic populations, according to the scientists.

“These types of studies are critical if we are to build on our previous success employing genetics to develop new, personalized therapeutics for IBD and using them to treat those most likely to respond well. In other words, getting the right therapy to the right patient at the right time,” said McGovern, who holds the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics at Cedars-Sinai.

Funding: This work was supported in part by the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (grants P01 DK046763 and U01 DK062413), and The Leona M. and Harry B. Helmsley Charitable Trust.

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai. 

“The goal of this consortium is to create a hub for innovation that propels stem cell science from the laboratory to the bedside,” said Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine, who initiated this new collaboration.

Regenerative medicine uses both gene therapy and stem cell technologies to regenerate tissues within the body to potentially treat a number of incurable diseases.  

More than 100 people, including the directors of major stem cell institutions, attended a recent three-day summit. The organizations agreed to work together to accelerate novel regenerative medicine therapies. 

Summit attendees also included leaders of the California Institute for Regenerative Medicine (CIRM), which was created through a voter-approved ballot measure signed into law in 2004. CIRM distributes funding for regenerative medicine-related studies. 

The group discussed collaborating on stem cell and gene therapy manufacturing programs, educational courses, core services to support the science, scientific innovations, and new regenerative medicine clinical trials.

The following CIRM-funded organizations are part of the new stem cell consortium:

• Cedars-Sinai Board of Governors Regenerative Medicine Institute
• University of California, Santa Barbara, Center for Stem Cell Biology and Engineering
• Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the University of Southern California
• University of California, Riverside, Stem Cell Center
• University of California, Irvine, Sue and Bill Gross Stem Cell Research Center
• UCLA Broad Stem Cell Research Center
• City of Hope
• California Institute of Technology

Representatives from these partnering organizations plan to convene annually to discuss collaborative projects and accelerate regenerative medicine projects in California.

“The consortium is a testament to the importance of regenerative medicine to the field of medicine, as a whole,” said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs, dean of the Medical Faculty, and the Helene A. and Philip E. Hixon Distinguished Chair in Investigative Medicine at Cedars-Sinai. “Initiating this consortium is also a reflection of the care with which we steward critical funds from grantees like CIRM.”

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai. 

Targan, who holds the Feintech Family Chair in Inflammatory Bowel Disease and is director of the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, was recently named by Research.com as one of the best immunology scientists, in recognition of his authorship of over 500 publications in the immunology field alone.

Cedars-Science spoke with Targan about how his work has advanced the field of immunology and the next frontiers in IBD research.

How did you become interested in the field of immunology?

I published my first paper as a high school student working in a gastroenterology lab at UCLA in the 1960s. After medical school, I was particularly interested in IBD because, throughout my internship and residency, nothing was known about the disease. I pursued a combination GI and immunology fellowship when not many people were doing that.

Early on, while I was still in my fellowship, I got my own lab looking into the intestinal mucosa and elucidating molecular mechanisms of natural-killer T-cells, which control inflammation and regulate the microbiome in the gut. As I got more and more into this work, I was also working as an attending physician. You always hear about “bench to bedside,” but it works the other way around, too. IBD is very complex, and through observing patients, I knew we had to crack a very complex disease that was not yet understood.

What is the history of the Cedars-Sinai approach to IBD?

I got lucky at a young age, and in 1989 I was the first clinician-scientist to be selected as chair of the Crohn’s and Colitis Foundation of America National Scientific Advisory Committee. A group of us met for a summit in Palm Springs to put together a roadmap for a new multidisciplinary approach that changed everything and was embraced by the National Institutes of Health (NIH) and pharmaceutical companies. We documented the genetic heterogeneity of IBD: the many different expressions, the importance of the microbiome and genetics, and how we needed to develop precision medicine. We recognized we needed to study patient populations that shared similarities, including the molecular mechanism causing their disease.

In 1992, I came to Cedars-Sinai with NIH grants to build a multidisciplinary IBD center. We started a biobank of patient information and concentrated on genetic biomarker and biological function discovery, so we could categorize patients based on how we know they would respond to certain drugs. I love that our integrated science is being tried and taken up everywhere.

What is your role in the discovery of biologic drugs for IBD?

We were studying TNF, a protein involved in Crohn’s disease, and discovered an antibody that blocked TNF induction of proinflammatory modes. We put all the complex science together, using the biobank as the glue, and in 1996, we led the first trial of a biologic therapy to target TNF. This was the beginning of the biologic era in IBD.

Why is it so critical to develop partnerships in the pharmaceutical industry?

Most academics don’t know how to move their science toward the ultimate target: a drug to go into a patient. That has always been my goal, but it takes a different talent to run a startup. I started a drug discovery and development unit to bring scientists from industry into academic research; that bridge was necessary. When I gathered the right really smart, talented people, led by Janine Bilsborough and including leading geneticist Dermot McGovern, everything fell together. We were able to develop a molecule that directly affected scarring in ulcerative colitis and Crohn’s and is highly concentrated in the gut mucus. Because we had the biobank, we had a drug that was shown to be successful, and we had a pipeline to discover more drug targets. It was just a vision, and now it’s a reality, and it’s only going to expand the field for all autoimmune conditions.

What remains to be known about IBD?

Today, our biggest work focuses on treatment durability and understanding why some people stop responding to a drug they’ve been successfully treated with for years. It’s not just their genetics or because their body developed antibodies, but rather because of another mechanism we don’t yet recognize. We’re now focused on developing IBD scores and treatment “menus” to deal with dominant disease pathways.

Additionally, we need to understand why some people develop IBD after certain environment exposures, including stressful events. We’re just starting, and I’m not young anymore, but I very much want to see this lane open up.

What is your most important contribution to the field of immunology?

So many brilliant, high-quality clinical scientists who have trained at Cedars-Sinai have moved on to do amazing things in industry or to lead major programs and organizations around the world. The number one thing I’ll look back on in my career is the pleasure I’ve had in mentoring physicians and scientists.

Sudden cardiac arrest occurs when the heart stops beating. It causes at least 300,000 deaths in the U.S. each year. Most people die within 10 minutes of cardiac arrest. Some people survive if they can get CPR chest compressions or shocks with a defibrillator right away.

“If a person has a family member who has suffered sudden cardiac arrest, it may be helpful to undergo genetic testing to help understand one’s own risk for experiencing this dangerous condition,” said Evan Kransdorf, MD, PhD, assistant professor of Cardiology in the Smidt Heart Institute at Cedars-Sinai and senior author of the study.

Scientists are finding that some forms of sudden cardiac arrest can be prevented with an implantable defibrillator, whereas other forms of the condition aren’t responsive to interventions like defibrillators and shocks.

The condition is rare in people under the age of 35. Sudden cardiac arrest is, however, the top cause of death among young athletes.

Previous studies have found that between 12%-30% of children and young adults who experienced sudden cardiac arrest carry certain genetic variants that may have put them at higher risk for the condition.

But Kransdorf said a true figure is difficult to determine because most studies have relied on studying blood samples collected from survivors or their family members by specialized referral clinics. These samples, he said, aren’t representative of the U.S. population.

For this study, investigators analyzed blood samples collected through two ongoing community-based studies of sudden cardiac arrest: the Oregon SUDS and Ventura PRESTO studies. These are longstanding community-based programs established by Sumeet Chugh, MD, director of the Center for Cardiac Arrest Prevention in the Smidt Heart Institute and the Pauline and Harold Price Chair in Cardiac Electrophysiology Research.

As part of these studies, first responders collect blood samples from people who experience sudden cardiac arrest in Portland, Oregon, and Ventura County, California.

Investigators performed whole-genome sequencing on blood samples collected from 52 people age 21 and under who experienced sudden cardiac arrest. They found that two of the 52 young people carried genetic variants that previous studies have found to be highly associated with the condition. Four of the young people carried variants that might play a role in increasing risk for the condition, but the significance of these variants is still unknown.  

The rate of genetic variants in this population was lower than those found in other studies.  

“Additional community-based studies are going to be important to help us understand how the genetics of a diverse population compare with what has been previously established in the medical literature through studying more referral-based populations,” said Chugh.

Kransdorf, Chugh and colleagues at the Center for Cardiac Arrest Prevention are currently analyzing data from a sample of more than 3,000 people who experienced sudden cardiac arrest. They seek to better understand the extent to which genetic variants contribute to the condition.

Other Cedars-Sinai investigators who worked on the study include Lauri Holmstrom, MD, PhD, a visiting postdoctoral scientist; Kotoka Nakamura, PhD, a project scientist and team leader with the Center for Cardiac Arrest Prevention; Harpriya Chugh, a clinical research data specialist; Audrey Uy-Evanado, MD, a project scientist and team leader with the Phenotyping Core; and Faye Norby, PhD, a research assistant professor in the Department of Cardiology.

Funding: The study was funded by the National Institutes of Health (award number R01HL145675); National Heart, Lung and Blood Institute grants (R01HL147358); the Sigrid Jusélius Foundation; the Finnish Cultural Foundation; the Instrumentarium Science Foundation; the Orion Research Foundation; and the Paavo Nurmi Foundation. 

Read more in Discoveries: 3D Cameras Could Help Diagnose Rare Genetic Diseases