Research | Mount Sinai Today

Pioneering Discoveries in Inflammatory Bowel Disease

Nov 5, 2019 | Featured, Gastroenterology, Research

Precise cell types that correlate with a patient’s resistance to the standard therapy for Crohn’s disease—anti-inflammatory drugs called TNF inhibitors—have been identified for the first time by researchers at the Icahn School of Medicine at Mount Sinai and published in the September 5, 2019, issue of Cell. TNF inhibitors are used in Crohn’s disease to stop inflammation, but as many as 30 percent of patients do not respond to this treatment and require surgical intervention within 10 years after diagnosis. The new discovery could open the door to identifying biomarkers and tailoring better therapeutic options for these patients.

At the same time, two studies in the September 26, 2019, issue of The New England Journal of Medicine validate effective therapies for patients with treatment-resistant ulcerative colitis (UC), a chronic inflammatory disease of the large intestine. Both of these studies were led by Bruce E. Sands, MD, the Dr. Burrill B. Crohn Professor of Medicine and Chief of the Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai.

The results of Dr. Sands’ first clinical trial validated ustekinumab as a UC therapy. In the phase lll clinical trial, Dr. Sands and his team tested more than 900 patients with moderate-to-severe UC who were unable to tolerate or had an inadequate response to TNF inhibitors. The results from this trial led the U.S. Food and Drug Administration in October to approve ustekinumab for adult patients with moderately to severely active ulcerative colitis. Ustekinumab had previously been approved for treating patients with Crohn’s disease.

The second study was the first ever head-to-head comparison of two biologic therapies for inflammatory bowel disease: vedolizumab and adalimumab. In total, 769 participants with moderate to severe UC were recruited for this randomized phase 3b study, with 383 patients receiving 300 mg of vedolizumab intravenously at weeks 0, 2, and 6, then every 8 weeks, and with subcutaneous placebo injections, and 386 receiving placebo intravenously and adalimumab subcutaneously (160 mg week 1, 80 mg week 2, and then 40 mg every 2 weeks).

Researchers found that patients who received vedolizumab achieved significantly higher week 52 clinical remission rates than patients who received adalimumab (31.3% versus 22.5%) and endoscopic improvement (39.7% versus 27.7%). The remission rates for both therapies were similar among the 20% of participants who had previous exposure to TNF inhibitors.

In the study in Cell, Mount Sinai researchers used single-cell RNA sequencing and CyTOF technology to examine inflamed and noninflamed small intestine tissue samples as soon as they were removed from Crohn’s disease patients. Looking at the lesions in real time on a single-cell level, the investigators identified the immune cells and the circulating blood cells and their interactions, and mapped a landscape of thousands of cells in the lesion.

“Single-cell profiling provides unprecedented information on the make-up of the disease,” says co-corresponding author Miriam Merad, MD, PhD, Director of the Precision Immunology Institute and the Human Immune Monitoring Center at the Icahn School of Medicine at Mount Sinai. “This type of analysis will help us understand why patients respond to or resist specific treatment and what else we could
be targeting.”

Co-corresponding author Judy H. Cho, MD, Director of The Charles Bronfman Institute for Personalized Medicine, and Ward-Coleman Professor of Translational Genetics and Medicine at the Icahn School of Medicine at Mount Sinai, says, “We designed this study in a way that defines inflammation with unprecedented precision using immunology and computational biology to get a better understanding of this disease.”

Computational biologist Ephraim Kenigsberg, PhD, Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, and co-corresponding author of the Cell study, says, “Single-cell analysis revealed different cellular signatures, and when we integrated this with larger data sets, including clinical trials, we were able to make our findings clinically relevant.”

Landmark Study on Aspirin for High-Risk Heart Patients Is Led by Mount Sinai

Oct 21, 2019 | Cardiology, Featured, Research

Roxana Mehran, MD, center, principal investigator of the TWILIGHT study, with leading collaborators in the study, from left, Annapoorna S. Kini, MD; Valentin Fuster, MD, PhD; Juan J. Badimon, PhD; George Dangas, MD, PhD; Usman Baber, MD, MS; and Samin K. Sharma, MD.

High-risk patients who have undergone a coronary stent procedure may not require long-term aspirin, according to a groundbreaking global study led by Roxana Mehran, MD, Director of the Center for Interventional Cardiovascular Research and Clinical Trials, Mount Sinai Heart, and the Mount Sinai Professor in Cardiovascular Clinical Research and Outcomes, Icahn School of Medicine at Mount Sinai.

“We showed that withdrawal of aspirin after three months in patients already on ticagrelor, a potent antiplatelet regimen, reduced bleeding significantly without the harm of increasing death or heart attacks,” says Dr. Mehran, global principal investigator of “Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention” (TWILIGHT), which was published in September 2019 in The New England Journal of Medicine.

Says Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital, “I am proud of our team for achieving such great success with our collaborators in the United States and around the world on this pioneering clinical trial.”

The study addresses long-standing questions about the treatment of high-risk patients after percutaneous coronary intervention (PCI), also known as angioplasty, which opens blocked arteries and restores normal blood flow to the heart. “The same patients who are at high risk for ischemic events—such as heart attack or stroke caused by blocked blood vessels—are also at high risk for bleeding events,” says Dr. Mehran. “You have to find the right balance in therapies, and it is not easily found.”

In the current standard of care, high-risk patients who have received a cardiac stent are advised to take dual-antiplatelet therapy (DAPT)—both aspirin and a drug from a class of strong antiplatelet medications called P2Y12 inhibitors, of which ticagrelor is one. These two medications prevent heart attack or stroke by reducing the risk of blood clots. DAPT combines two drugs with similar effects, Dr. Mehran says, like using both “a shotgun and slingshot” for self-defense. TWILIGHT examined the impact of taking ticagrelor alone versus ticagrelor plus aspirin on clinically relevant bleeding among high-risk patients.

Investigators enrolled 9,006 patients at 187 sites in the United States, Canada, Europe, and Asia. They were high risk, meaning they met criteria such as having long or complex lesions in coronary arteries, or disorders such as diabetes or chronic kidney disease. All patients had undergone PCI with at least one drug-eluting stent and were prescribed aspirin and ticagrelor. After a three-month course of DAPT, the 7,119 patients without major adverse events were randomized to take either DAPT or ticagrelor with a placebo for 12 months. Among patients who took DAPT, 7.1 percent had major bleeding, compared with 4 percent of those who took ticagrelor and a placebo, and there was no difference in the risk for heart attack, death, or stroke between the groups. “This simpler approach saved many bleeding events and preserved the benefit of the single potent blood thinner,” says Usman Baber, MD, MS, Assistant Professor of Medicine (Cardiology), Icahn School of Medicine, who was lead author of the study with Dr. Mehran, and Chair of the TWILIGHT Clinical Coordinating Center.

The results were corroborated by a sub-study led by Juan J. Badimon, PhD, Professor of Medicine (Cardiology), and Director of Atherothrombosis Research at Mount Sinai Heart. Using a tool he is renowned for developing, the Badimon Chamber, researchers measured the thrombogenicity or “stickiness” of the blood in a group of 42 TWILIGHT patients, testing samples taken before and after they completed the 12-month treatment. Like the clinical study, the study of blood samples found that withdrawing aspirin caused no additional clot formation.

“The findings are particularly important and have the potential to change PCI practice,” says a co-author of the TWILIGHT study, Samin K. Sharma, MD, Director of Clinical and Interventional Cardiology at The Mount Sinai Hospital, and Anandi Lal Sharma Professor of Medicine in Cardiology.

Dr. Mehran expressed profound gratitude to Mount Sinai, which was the global sponsoring organization of TWILIGHT. “This study gives you an idea of the things we are able to do as an institution,” she says, “bringing together all of our resources to answer important questions for physicians and enhance the outcome for patients.”

The drug ticagrelor is made by AstraZeneca, which provided Mount Sinai with an unrestricted grant to perform the investigator-initiated study. Dr. Mehran has received financial compensation as an advisory board member for AstraZeneca in the past, and she and Dr. Baber have received consulting fees from AstraZeneca in the past.

Postdoctoral Award Supports Female Research Scientists

Oct 21, 2019 | Featured, Research

Scott L. Friedman, MD, with Shuang (Sammi) Wang, PhD

Two early-career scientists—Pinar Ayata, PhD, and Shuang (Sammi) Wang, PhD—are the recipients of the 2019 Robin Chemers Neustein Postdoctoral Fellowship Award, it was announced recently. Each will receive an award of $25,000 to further their research endeavors.

Intended to encourage and support female research scientists at the Icahn School of Medicine at Mount Sinai, the fellowship was established in 2010 through a generous gift from Robin Chemers Neustein, JD, MBA, a former member of Mount Sinai’s Boards of Trustees. Recipients are senior postdoctoral scientists who intend to complete their training within two years, have demonstrated high-impact accomplishments in biomedical sciences, and exhibit the potential for an independent scientific career.

Dr. Ayata works in the laboratory of Anne Schaefer, MD, PhD, in The Friedman Brain Institute within the Nash Family Department of Neuroscience. She is uncovering the molecular mechanisms by which a type of cell known as microglia support health and function of the brain, and how their dysfunction contributes to neurodegenerative disease.

“Pinar is an extraordinary young scientist with a knack for exciting and novel ideas and the tenacity to follow through,” says Dr. Schaefer, Associate Professor of Neuroscience, and Psychiatry. “She is firmly in the group of young investigators likely to lead the field of neuroscience in the near future.”

Anne Schaefer, MD, PhD, left, with Pinar Ayata, PhD

Dr. Wang works in the laboratory of Scott L. Friedman, MD, Chief of the Division of Liver Diseases. Her research is focused on investigating how a specialized group of chemical modifications of DNA alter the activity of scar-producing cells in the liver that contribute to cirrhosis (advanced scarring) of this organ.

“Sammi is a wonderful investigator and generous team member whose superb science and attention to detail complement great intelligence and maturity,” says Dr. Friedman, who is also Dean for Therapeutic Discovery and Fishberg Professor of Medicine. “She is a joy to have as a colleague and has a very bright future.”

Study Directly Ties Caloric Intake to Inflammation

Sep 24, 2019 | Featured, Research

Researchers at the Icahn School of Medicine at Mount Sinai, using sophisticated, single-cell technology,have isolated the molecular underpinning that explains why short-term fasting and a low-calorie diet are beneficial to people with inflammatory and autoimmune diseases, such as atherosclerosis and rheumatoid arthritis. Until now, the connection between reduced caloric intake and improved health has been a widely held but poorly understood hypothesis that has captured the public’s attention as high-profile celebrities attest to the success of frequent fasting.

In the new study, published in the August 22, 2019, issue of Cell, the researchers, led by Miriam Merad, MD, PhD, Director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, were able to describe how dietary intake actually controls the quality and quantity of monocytes—a particular group of white blood cells.

The scientists found a direct link between the amount of glucose and protein in the body and the number of circulating monocytes. These white blood cells, likened to military “reserve forces,” respond to inflammatory stimuli and also play a major role in metabolic equilibrium, growth, and other processes. When digestible carbohydrates, protein, and fat were removed from the diet, the investigators found the pool of circulating monocytes decreased. Importantly, the size of the monocyte pool that was circulating in the blood depended upon the amount of carbohydrates ingested.

The study profiled 12 healthy, normal-weight volunteers 3 hours after eating and 19 hours after fasting, as well as mice that had fasted for 4 hours.

“Monocytes are highly inflammatory immune cells that can cause serious tissue damage,” says Dr. Merad. “We have seen more of these monocytes in blood circulation as Western-style eating habits have been adopted by increasing numbers of people around the world. Now that we have a better understanding of what is driving this incidence, we can work to treat it more effectively.”

Stefan Jordan, PhD, the study’s first author and a postdoctoral fellow in the Department of Oncological Sciences at the Icahn School of Medicine at Mount Sinai, says, “There is enormous potential in investigating the anti-inflammatory effects of fasting, considering the broad spectrum of diseases that are caused by chronic inflammation. Our discoveries could lay the groundwork for novel treatments in the future.”

Indeed, chronic diseases such as type 2 diabetes, metabolic syndrome, and cardiovascular disease are believed to be mostly caused by chronic inflammation. According to a study by the RAND Corp., 60 percent of Americans had at least one chronic condition and 42 percent had multiple chronic conditions as of 2014, the last year for which this data was available. In 2018, the Milken Institute released a report that stated the most common chronic diseases cost the U.S. economy more than $1 trillion annually.

One of the study’s important findings was that short-term fasting did not compromise the body’s ability to protect itself from acute infections or repair tissue, whereas starvation for 48 hours prior to infection did compromise the body’s antimicrobial immunity and ability to repair tissue.

Another finding by Dr. Merad and her team was that by activating a key cellular pathway in the liver, AMPK, they were able to regulate the number of monocytes regardless of caloric intake.

“Targeting liver energy sensors could be an innovative strategy for the prevention and treatment of chronic inflammatory and autoimmune diseases,” says Dr. Merad.

Study Finds Distress Among Children in Immigrant Detention

Sep 24, 2019 | Engagement, Featured, Psychiatry, Research

The research team from the Icahn School of Medicine at Mount Sinai included, from left, Priscilla O. Agyeman, MPH, research coordinator, Division of Liver Diseases; Principal Investigator Craig L. Katz, MD; and Sarah MacLean, third-year medical student.

Mount Sinai researchers found that children being held in an immigration detention center experienced high levels of mental health distress, with 44 percent demonstrating at least one significant emotional or behavioral symptom. The report was the first large, empirical study examining the mental health of children in U.S. immigration detention, says the Principal Investigator, Craig L. Katz, MD, Clinical Professor of Psychiatry, Global Health, and Medical Education, Icahn School of Medicine at Mount Sinai.

“Perhaps our findings should not really be a surprise,” says Dr. Katz, who considers the study a valuable baseline for further research. “Kids who had been previously separated from their parents had higher rates of emotional problems, compared to those who were always detained with a parent. And the detained children overall had higher rates of distress compared to the general population in the U.S.”

The research team from Mount Sinai spent two months in summer 2018 at a detention center in the Southwestern United States. speaking to women and children, most of whom had fled Honduras, Guatemala, or El Salvador. The researchers were not allowed to use telephones or take photographs while interviewing the families in a visitation trailer. The study was published in June 2019 in the journal Social Science and Medicine.

The mothers told stories of escaping gang violence or domestic violence in their home countries, where government and police officials often turned a blind eye. The team interviewed 425 women about their eldest child, using the standard Parent-Report Strengths and Difficulties Questionnaire. Among those 425 children, 32 percent had elevated scores for emotional problems, and the rate was 49 percent for those who had previously been separated from their parent. A subset of 150 children who were age 9 or older also completed the UCLA Post-Traumatic Stress Disorder Reaction Index. Seventeen percent of those children had a probable diagnosis of PTSD, compared with 4.7 percent in the general population of U.S. children.

“Children with emotional distress showed symptoms like wanting to cry all the time; problems with conduct, such as fighting with other kids or having temper tantrums; and peer problems like not having a lot of friends or only wanting to interact with adults,” says Sarah MacLean, lead author of the study and a third-year medical student at the Icahn School of Medicine who was part of the field team. “The children with symptoms of PTSD reported having flashbacks or nightmares about a trauma, or feeling depressed or sad.”

The field research for the study was conducted by Kim A. Baranowski, PhD, Associate Director of the Mount Sinai Human Rights Program; Priscilla O. Agyeman, MPH, a research coordinator in the Division of Liver Diseases, Icahn School of Medicine; Ms. MacLean; and Joshua Walther, a fourth-year medical student at the University of Texas Health Science Center in San Antonio, Texas. Authors of the report were the field team; Dr. Katz; and Elizabeth K. Singer, MD, MPH, Assistant Professor of Emergency Medicine, and Medical Education, Icahn School of Medicine, and Director of the Mount Sinai Human Rights Program.

Dr. Katz hopes to expand on the research, which had certain limitations. The subjects were a “convenience sample,” meaning they were the families who were accessible for interviews in the center’s visitation trailer, as opposed to a randomly selected sample. Because of the setting, some mothers completed the forms in their child’s presence, which may have influenced their responses.

The study also could not pinpoint the cause of the children’s distress, whether it was detention, or the journey to the U.S. border, or the violence they faced in their home countries, says Dr. Katz, who is also an Associate Director of the Mount Sinai Human Rights Program. Regardless of the cause, the study concluded that the children “would benefit from culturally responsive and trauma-informed mental health care.” Dr. Katz says that ideally, the mothers and children would receive appropriate psychiatric support once they settle into a community. “But even if they don’t get psychiatric help, social support helps,” he says. “Making sure people have clothes, a backpack, a phone, know how to take a bus. That support is going to make an enormous different in the trajectory of their recovery.”

Despite their higher rates of emotional distress, 98 percent of the children studied had normal scores on the “prosocial” scale, which included being considerate of other’s feelings and volunteering to help others. The team found signs of hope and humanity at the center, a broad expanse of trailers surrounded by a barbed wire fence. One boy from Honduras drew a picture and shyly presented it to Ms. Agyeman, and she intends to keep it forever. “The picture gave me a bittersweet message,” she says, “that a little boy can do the things any other kid would do, laughing and playing, even in an otherwise very sad environment.”

Listen to a Road to Resilience podcast on the Immigrant Detention study.

Awards Ceremony Honors Exceptional Mount Sinai Faculty

Updated on Jun 30, 2022 | Featured, Research

Back row: Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai, and President for Academic Affairs, Mount Sinai Health System, right, and Joanne Stone, MD, MS, Faculty Council President and Professor of Obstetrics, Gynecology and Reproductive Science, left, presided over the Faculty Awards ceremony. Honorees included, front row, from left: Lauren Peccoralo, MD, MPH; Jeffrey Laitman, PhD; Christina Weltz, MD; Nathan Kase, MD; and Chitra Upadhyay, PhD; back row, starting second from left: Juan Wisnivesky, MD, DrPH; Madhav Menon, MD; Gaelle Doucet, PhD; Florian Krammer, PhD; and Ari Greenspan, MD.

The annual Faculty Awards ceremony recently recognized 14 outstanding physicians, researchers, and educators of the Icahn School of Medicine at Mount Sinai. Honorees included senior faculty who have made significant contributions to Mount Sinai and to their fields, as well as junior faculty who have demonstrated exceptional potential in the early stages of their careers in medicine and science.

The Honorees:

Faculty Council Lifetime Achievement Awards: Nathan Kase, MD, Dean Emeritus and Professor of Obstetrics, Gynecology and Reproductive Science; and Jeffrey Laitman, PhD, Distinguished Professor of Medical Education

Faculty Council Senior Faculty Awards: Andrew Hecht, MD (Orthopedics); Florian Krammer, PhD (Microbiology); Christina Weltz, MD (Surgery); and Juan Wisnivesky, MD, DrPH (Medicine)

Faculty Council Junior Faculty Awards: Lauren Peccoralo, MD, MPH (Medicine); and Junqian Xu,PhD (Diagnostic, Molecular and Interventional Radiology)

Dr. Harold and Golden Lamport Research Awards (Basic Research): Ian Maze, PhD (Neuroscience); and Chitra Upadhyay, PhD (Medicine); (Clinical Research): Gaelle Doucet, PhD (Psychiatry); and Madhav Menon, MD (Medicine)

Solomon Silver Award in Clinical Medicine: Ari Greenspan, MD (Medicine)

Special Faculty Council Award of Appreciation: Tanvir Choudhri, MD (Neurosurgery)

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