Mar 10, 2020 | Featured, Research
Jason C. Kovacic, MD, PhD; back row center, and Jeffrey W. Olin, DO, second from right; with team members, from left, Daniella Kadian-Dodov, MD; Annette King, NP; Bhargavi Vonguru, MSc; and Valentina d’Escamard, PhD.
A Mount Sinai team has gained valuable insights into fibromuscular dysplasia (FMD), a disorder of the arteries that is typically diagnosed in otherwise healthy women at midlife and sometimes causes aneurysms or serious heart disease. The findings could open the door to new strategies for the diagnosis, treatment, and management of FMD, including a blood test that could lead to earlier diagnosis.
“A lot of work remains, but we have proved that a reliable, blood-based test for this disease is eminently possible,” says Jason C. Kovacic, MD, PhD, Professor of Medicine (Cardiology), Icahn School of Medicine at Mount Sinai, and corresponding author of a study published in August 2019 in Cardiovascular Research. “Such a test could have an enormous impact on the management of FMD. It could pave the way for screening and counseling of family members, and for tailoring clinical care to patients who, in many cases, remain undiagnosed until they suffer a major event.”
The team compared blood samples from 90 women with FMD and 100 women without it, evaluating nearly 1,000 proteins and 31 lipid subclasses. Eventually, researchers identified and validated 37 proteins and 10 lipid sub-classes that make up a unique FMD disease signature. Then, machine learning was used to develop a prototype blood test for FMD.
Fibromuscular dysplasia (FMD) can affect arteries throughout the body. Arteries to the kidney of a patient with FMD, left, have a “string of beads” appearance, compared with normal arteries, right. A team at Mount Sinai is in the early stages of developing a blood test for the disease, which can cause aneurysms, heart attacks, or stroke.
“This is preliminary, but it is the first meaningful, mechanistic research that has been done in this disease,” says Jeffrey W. Olin, DO, Professor of Medicine (Cardiology), Icahn School of Medicine, and a co-author of the study. Developing an accurate test is crucial, says Dr. Olin, a leader in the treatment of FMD. “It’s not uncommon for a patient to have high blood pressure related to FMD that started when she was 30, and not have FMD diagnosed until she is 50,” he says.
FMD is a genetic disease that predominantly affects women and can strike at any age, although the average age of patients at diagnosis is 52. Abnormal cells form in the arteries, which take on a characteristic “string of beads” appearance, causing narrowing, tearing, or bulging of the vessels.
“FMD can affect the arteries of the kidney, causing high blood pressure. It can affect the arteries to the brain, which can cause stroke, or it can affect the arteries in the heart, in which you can develop a heart attack,” Dr. Olin explains. The prevalence of the disease is hard to gauge, because most patients with FMD have no symptoms for many years, and it is often found in a scan for another clinical purpose. For example, “FMD is discovered in approximately 4 percent of potential kidney donors, but this may be a serious underestimation of its prevalence,” he says.
Mount Sinai is in the forefront of efforts to unravel the genetics of FMD, due to the work of Dr. Kovacic and Dr. Olin, who is principal investigator for the United States Registry for Fibromuscular Dysplasia, and Director of the Mount Sinai Heart Center for Fibromuscular Dysplasia Care and Research. The team also includes Daniella Kadian-Dodov, MD, Assistant Professor of Medicine (Cardiology); Valentina d’Escamard, PhD, a senior scientist in the Kovacic Lab; and Annette King, NP, study coordinator.
“We are looking for a genetic profile of this disease, and we do have some promising preliminary results,” Dr. Olin says. “But ultimately, we want to find the gene or genes that cause this disease, and develop a treatment that blocks the effects of those genes.”
Updated on Jun 30, 2022 | Research
The higher a mother’s exposure to particulate air pollution during pregnancy, the lower her baby’s heart variability will be in response to stress at 6 months of age. That was the novel conclusion of a study published in the October issue of Environmental Health Perspectives, led by Rosalind J. Wright, MD, MPH, Dean for Translational Biomedical Research.
The study is believed to be the first of its kind in suggesting that environmentally induced changes in the mother may translate to the intrauterine environment.
In adults, decreased heart variability is a known risk factor for cardiovascular disease; chronic diseases such as diabetes, hypertension, and obesity; and mental health problems, including depression and anxiety disorders.
Critical components of the autonomic nervous system develop and mature during gestation. Variability in how the heart rate responds to stressful experiences is essential for maintaining optimal functioning in humans. The researchers studied 237 Boston-based mothers and their infants and used satellite data and air pollution monitors to determine the levels of the mothers’ exposure during pregnancy.
“These findings, in combination with increasing worldwide exposure to particulate air pollution, highlight the importance of examining early life exposure to air pollution in relation to negative medical, developmental, and psychological outcomes,” says Dr. Wright, Co-Director of the Institute for Exposomic Research at Mount Sinai, who also holds the Horace W. Goldsmith Professorship in Children’s Health Research, Icahn School of Medicine at Mount Sinai.
“A critical step in identifying children at risk for costly chronic disorders is identifying exposures that lead to early vulnerability.”
Updated on Jun 30, 2022 | Cancer, Featured, Research
From left: Thomas Marron, MD, PhD; Adeeb Rahman, PhD, Associate Professor, Genetics and Genomic Sciences; and Miriam Merad, MD, PhD
Using a collection of sophisticated single-cell technologies, scientists at the Mount Sinai Health System have launched an early-stage clinical trial that examines the effects of immunotherapy on hepatocellular carcinoma, non-small-cell lung cancer, and head and neck squamous cell carcinoma.
Four to six weeks before a tumor is resected, the researchers administer a neoadjuvant immunotherapy, cemiplimab, and study its effects. As soon as the tumor is removed, they continue to analyze the fresh tissue for a month or more to observe mechanisms of resistance and response. The Phase 1 trial is sponsored by Regeneron Pharmaceuticals, Inc.
“With the technologies available to us at The Tisch Cancer Institute and Mount Sinai’s Human Immune Monitoring Center, we are able to investigate at an unprecedented depth how these immune therapies are changing the microenvironment within the tumor,” says Thomas Marron, MD, PhD, Assistant Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai, and Principal Investigator of the study. “This trial enables us to analyze fresh tissue immediately after resection—instead of the preserved tissue typically obtained in trials—to observe the dynamic changes that occurred.”
The study is enrolling multiple small cohorts of 21 patients. One goal is to determine which cancer patients will benefit from cemiplimab, and, more specifically, how cemiplimab can be more effective by combining it with chemotherapy and/or other novel immunotherapies. Cemiplimab was previously studied at Mount Sinai in liver and lung cancer patients and has been approved by the U.S. Food and Drug Administration for patients with metastatic cutaneous squamous cell carcinoma. The compound works by inhibiting the interaction between PD-L1, a protein on the surface of tumor cells, and PD-1, the protein on the surface of T cells, and restoring the immune system’s ability to recognize and kill cancer cells.
Another goal of the study is to identify biomarkers in human tissue and blood that will be able to predict who will respond to immunotherapy, since so many patients do not respond to anti-PD-1 therapy. “We really need to find the ideal patients to treat so we don’t unnecessarily expose those who won’t respond to the toxicity of immune therapies,” says Dr. Marron, who is also Assistant Director of Early Phase and Immunotherapy Clinical Trials at Mount Sinai. “There’s also a financial issue at stake for patients and society in general in using expensive drugs that are not improving outcomes.”
Dr. Marron and his team are using several powerful new technologies to help them with their work. These include immune mapping and monitoring technologies such as mass cytometry (CyTOF), a flow-cytometry-like technology that allows them to see up to 50 proteins on each cell so they can identify the cell type and classify the maturation and activation status of the cell, along with some of the regulatory “on/off” checkpoints.
CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) is another platform that provides an even higher resolution view of each individual cell within the tumor. This technology combines the capabilities of CyTOF and single-cell RNA sequencing to characterize both the RNA and protein in each cell.
A third technology is known as Multiple Ion Beam Imaging (MIBI), a unique form of immunohistochemistry that allows scientists, for the first time, to unravel the spatial architecture of tumors in order to better understand the mechanisms through which the immune system is infiltrating the tumor and is being hijacked by the tumor.
“For 10 years, we’ve been building the Human Immune Monitoring Center into one of the leading platforms in the world for investigating the role of the immune system in human disease, and using that knowledge to design novel, immune-based therapies,” says Miriam Merad, MD, PhD, Director of the Center, and Professor of Oncological Sciences, and Medicine, Icahn School of Medicine at Mount Sinai.
Drawing on a highly specialized team of clinicians, immunologists, mathematicians, physicists, and surgeons, the Human Immune Monitoring Center is currently involved in more than 45 federal- and foundation-funded research programs in fields such as cancer, autoimmune disease, inflammatory bowel disease, allergies, and neurodegenerative disease.
Updated on Jun 30, 2022 | Featured, Research
Denise Cai, PhD
Denise Cai, PhD, Assistant Professor of Neuroscience, Icahn School of Medicine at Mount Sinai, is the recipient of a 2019 National Institutes of Health New Innovator Award to continue her novel research into the brain and memory.
The Award was established to accelerate the pace of biomedical, behavioral, and social science discoveries by supporting exceptionally creative early-career scientists with high-impact ideas. It provides Dr. Cai with $2.5 million in funding over five years.
Dr. Cai’s research is driven by two perplexing questions: How, precisely, does the brain optimize its capacity and efficiency to store memories? And, how do these processes change over time? She and her research team will use a number of innovative approaches to further explore these concepts.
The effort includes the recording of neural activity in the brains of both younger and older study mice as they learn new spatial locations through a novel, wire-free miniature microscope known as the Miniscope system, which was co-developed with colleagues at the University of California, Los Angeles, and the Icahn School of Medicine. Using this new technology, the mice will wear tiny, head-mounted, wire-free microscopes as they enter a variety of different environments, enabling researchers to record and analyze thousands of neurons over the course of time.
“We will use a variety of techniques to observe and manipulate these populations of neurons to determine how the neural activity in the brain controls the animals’ behavior,” explains Dr. Cai. “Ultimately, we aim to learn how the brain optimizes its capacity to store information across a lifetime. I am tremendously grateful to have received the New Innovator Award, which will enable our lab to explore some fundamental, yet very complex, biological questions in the field of memory and cognition.”
Updated on Jun 30, 2022 | Community, Research
From left: Theresa Lin and Sarah Simon, research assistants; Katherine Leaver, MD, Assistant Professor of Neurology, Icahn School of Medicine at Mount Sinai; Sonya Elango, genetic counselor; Susan Bressman, MD; Deborah Raymond, genetic counselor; and Rachel Saunders-Pullman, MD, MPH, MS, Associate Professor of Neurology, Icahn School of Medicine at Mount Sinai.
Physician-scientists from Mount Sinai Beth Israel and The Michael J. Fox Foundation highlighted new treatments and research in Parkinson’s disease during a “Thankfest” symposium and lunch in October. The event was held to recognize the valuable contributions of 60 special attendees—patients who volunteer to participate in clinical trials to advance understanding of Parkinson’s disease.
“Clinical trials are in a very exciting new phase of targeted treatments that include correcting specific genetic causes,” says Susan Bressman, MD, a renowned Parkinson’s disease clinician and researcher. Dr. Bressman is the Mirken Family Professor of Neurology and Director of the Movement Disorders Center.
“The only way we will know if these approaches work is by testing them in patients,” says Dr. Bressman. “The process depends on the altruism of patients, and they deserve giant kudos.”
Updated on Jun 30, 2022 | Research
From left, front row: Kurt A. Yaeger, MD, PGY-5; Travis R. Ladner, MD, PGY-4; Ian T. McNeill, MD, MS, Chief Resident; Emily Chapman, medical student; and Alejandro Carrasquilla, MD, PGY-3; middle row: Ernest J. Barthélemy, MD, MA, MPH, PGY-6; Joshua B. Bederson, MD; J Mocco, MD, MS; and Abhiraj Bhimani, MD, PGY-1; and back row: Trevor Hardigan, MD, PhD, PGY-2; Leslie Schlachter, PA-C; and Georgios Maragkos, MD, Pre-residency Fellow.
The Department of Neurosurgery at the Icahn School of Medicine at Mount Sinai received the first place award for most accepted abstracts by residents at the 2019 Congress of Neurological Surgeons (CNS) Annual Meeting, which took place in October in San Francisco.
The 77 accepted abstracts were featured as oral presentations and posters, covering a wide range of topics, including spinal surgery and trauma, intracerebral hemorrhage, skull base tumors, glioblastoma, pediatric epilepsy, and neurocritical care, as well as socioeconomic issues related to neurosurgical treatment. At the 2018 CNS meeting, the Department placed third, with 35 accepted abstracts.
“Our trainees are strongly supported to perform research by Neurosurgery Vice Chair and Residency Program Director J Mocco, MD, MS. They are extremely active in exploring ways to work with faculty to improve how we treat neurological diseases and conditions, and the number of accepted abstracts we had at this year’s CNS meeting is a testament to that,” says Joshua B. Bederson, MD, Leonard I. Malis, MD/Corinne and Joseph Graber Professor of Neurosurgery, and Chair of Neurosurgery, Mount Sinai Health System.
