Mar 8, 2017 | Research
Eyal Shemesh, MD, Associate Professor of Pediatrics
Researchers from the Icahn School of Medicine at Mount Sinai have found that supervised self-injection with empty syringes makes many food-allergic adolescents and their parents more comfortable with using the life-saving devices. The results were published on March 7 in The Journal of Allergy and Clinical Immunology: In Practice.
“Many adolescent patients with food allergies experience needle phobia or anxiety about self-administering epinephrine,” said the study’s lead author, Eyal Shemesh, MD, Associate Professor of Pediatrics at the Icahn School of Medicine at Mount Sinai. “Although it’s a simple idea for teenagers to practice giving themselves an injection to make themselves feel comfortable, this could lead to them being confident enough to take a life-saving action using epinephrine down the road.” The study’s senior author is Scott Sicherer, MD, Professor of Pediatrics, Allergy and Immunology at the Icahn School of Medicine at Mount Sinai.
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Mar 6, 2017 | Featured, Research
Julio Aguirre-Ghiso, PhD
New research from the Icahn School of Medicine at Mount Sinai has found that cancer cells can spread without the benefit of a primary tumor and remain dormant for months or even years before triggering aggressive, deadly breast cancer metastases. This surprising new model of early cell dissemination and metastasis appeared in the December 14, 2016, issue of Nature. It upsets the long-held scientific belief that tumors only spread from a pathologically defined and highly mutated invasive tumor. In fact, the findings revealed that a primary tumor may never develop.
“As a biologist who has been measuring tumors since I was 20 years old, this was, indeed, a very surprising finding,” says lead author Julio Aguirre-Ghiso, PhD, Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai. “It provides an alternative scenario for how metastases develop, and that could have a profound effect on our work going forward.”
Dr. Aguirre-Ghiso’s preclinical research, which focused on very early-stage breast cancer in animal models, was published with a companion paper authored by a team led by Christoph A. Klein, MD, at the University of Regensburg in Germany. The companion paper supported Mount Sinai’s findings with evidence of the same occurrence in human cancer cells and tumors.
This image captures early disseminating cancer cells in mouse models (cyan) moving toward blood vessels (red).
The studies’ new findings offer insights into several questions that have long puzzled scientists. First, why do as many as 10 percent of cancer patients worldwide have cancer metastases but no original tumor? Equally important, why is it so difficult to treat cancer that has spread? To that point, a key finding was that most early-spread cells remain dormant while most chemotherapeutic and targeted treatments are aimed at cells that are proliferative.
“Those cells that leave early can spend a long time without growing, or they can grow so slowly that any antiproliferative therapy will ignore them,” Dr. Aguirre-Ghiso says.
In women, the spread of early breast cancer cells is an extension of the normal process of creating a branching tree of breast milk ducts. Two major pathways are altered in the process: p38, a tumor suppressor, and HER2, an oncogene. As a mammary tree develops, p38 and HER2 are alternatively turned off and on, allowing cells to move through the mammary gland. In their experiments with mouse models, the researchers found that if HER2 is over-activated or switched on, and p38 is permanently turned off, cells are able to enter the bloodstream and travel to organs such as the lungs and bone marrow, where a growth switch can later activate the metastases.
With the help of a team of researchers from Albert Einstein College of Medicine, the Mount Sinai scientists were able to monitor the movement of oncogene cells that had been tagged with a fluorescent protein as they moved from the mammary tree to surrounding tissue and into the bloodstream. “It was quite amazing,” says Dr. Aguirre-Ghiso.
Developing full-scale biomarkers and mechanisms that can identify early-spread cells is a logical next step for Dr. Aguirre-Ghiso and his team. “If we had tests or imaging tools that could tell us in a minimally invasive way exactly where these cells are and if they’re evolving or growing, then we could take steps to eradicate them or keep them dormant,” he explains. “That kind of approach could truly be transformative.”
Mar 6, 2017 | Featured, Research
Study authors include, from left: Miriam Merad, MD, PhD; graduate student Aleksey Chudnovskiy; and Veronika Kana, postdoctoral fellow, MD, PhD.
The discovery of a novel type of microbe found in laboratory mice at the Icahn School of Medicine at Mount Sinai has shed new light on the existence of similar organisms in humans, which may help boost the immune system and protect against food-borne toxins, such as salmonella.
Scientists led by Miriam Merad, MD, PhD, Director of the Immunology Institute at the Icahn School of Medicine, described the discovery of the mouse microbe—called Tritrichomonas musculis (T. mu)—in the October 6, 2016, issue of Cell. Their findings suggest that a previously unknown set of single-cell organisms, or protists, which belong to a different biological classification than bacteria, live in the guts of mice and influence their immune system.
The significance of the Mount Sinai study was featured in a subsequent blog by Francis S. Collins, MD, PhD, Director of the National Institutes of Health, who commented: “Recently, we humans have started to pay a lot more attention to the legions of bacteria that live on and in our bodies because of research that’s shown us the many important roles they play in everything, from how we efficiently metabolize food to how well we fend off disease. As it turns out, bacteria may not be the only interior bugs with the power to influence our biology positively.”
Prior to the new findings, scientists considered protists similar to T. mu to be disease-carrying parasites. In fact, T. mu seemed to increase the number of tumors in mice with a genetic susceptibility for colon cancer and it increased weight loss and tissue damage in mice with preexisting inflammatory disease. But, the inflammation caused by a rapid increase in immune cells—dendritic and T cells—brought about by T. mu, led to beneficial results for mice, overall.
“Protists probably aren’t all bad when it comes to our health,” according to Dr. Collins. “As in the laboratory mice, they may afford us with extra immune protection, which could be especially beneficial for those living in parts of the world where infectious disease is an ever-present threat.”
Mount Sinai’s scientific team also included investigators from the National Institute of Allergy and Infectious Diseases, and Universidad del Rosario, Bogotá, Colombia. The study found that humans from around the world harbor a related microbe, Dientamoeba fragilis (D. fragilis). This protist—taken from the fecal samples from people in South America, Africa, Europe, and Asia—has been associated with irritable bowel syndrome, but its effects are not completely clear.
The scientists theorized that the absence of this microbe could also explain why some people are more susceptible to certain infections than others. In recent years, advances in DNA sequencing technologies have enabled scientists to identify and study previously unknown microbes that could not be studied in traditional laboratories for various reasons. This new field of study of the human microbiome aims to characterize these microbes and understand their role in supporting health and triggering disease.
“The most important result in this study is the finding that a nonbacterial bug in our flora could potentially protect from severe intestinal infections,” says Dr. Merad. “This illustrates the need to study non-bacterial species of the microbiome, including protists, which remain very prominent in the developing world.” Further study, she adds, will likely identify novel “crosstalks” or interactions between the microbiome and immune cells that impact health and disease.
Updated on Jun 30, 2022 | Featured, Research
An early-stage clinical trial has found that, compared to a placebo, a novel medication significantly reduces potentially life-threatening episodes of swelling of the airway as well as the hands, feet, and abdomen of patients affected by a rare genetic disorder. The findings were published in the New England Journal of Medicine.
Read the news release or watch the video.
Read additional news coverage in Science Daily.
Updated on Jun 30, 2022 | Featured, Research
From left: Martin John Walsh, PhD; and Stuart Sealfon, MD
Empirical evidence shows that exercise improves and prevents a large number of diseases, but the scientific basis and molecular mechanisms responsible for these beneficial effects are largely unknown. Two researchers at the Icahn School of Medicine at Mount Sinai have been awarded $15.5 million by the National Institutes of Health (NIH) Common Fund—designated as the Physical Activity Genomics, Epigenomics/transcriptomics Site (PAGES)—to advance this knowledge by mapping the molecular signals between different parts of the body during physical activity.
Stuart Sealfon, MD, the Sara B. and Seth M. Glickenhaus Professor of Neurology, Director of the Center for Advanced Research on Diagnostic Assays, and Chairman Emeritus of the Department of Neurology; and Martin John Walsh, PhD, Director for the Center of RNA Biology and Medicine, and a Professor of Pharmacological Sciences, Genetics and Genomic Sciences, and Pediatrics, will employ the latest genomic technologies in their investigation. They are part of a $170 million NIH program called the Molecular Transducers of Physical Activity Consortium (MoTrPAC), which involves more than two dozen academic research institutions around the country.
Using various genomic, epigenomic, transcriptomic, proteomic, and metabolomic technologies, Drs. Sealfon and Walsh, together with MoTrPAC, will analyze tissue and blood from 3,000 individuals in diverse racial, ethnic, gender, and age groups, and fitness levels. The samples will identify exercise-related chemical messengers and molecular responses that can provide the scientific basis for developing more effective individualized prescriptions of exercise, as well as the development of new drug therapies.
Where exercise has been studied, the benefits are measured in results such as less body fat, and lower cholesterol, sugar levels, and blood pressure. At molecular dimensions, the links between exercise and health remain mysterious.
“How is physical activity preventing or improving various cancers?” Dr. Sealfon asks. “We really don’t know the mechanisms.” The same holds true for Parkinson’s and Alzheimer’s diseases, depression, and other illnesses that have been shown in clinical studies to respond to exercise.
Based on their future findings, Drs. Sealfon and Walsh can foresee the creation of medications that mimic the signals released by exercising—so-called exercise mimetics—that would be particularly beneficial for patients with disorders that prevent or restrain their movement. According to NIH Director Francis S. Collins, MD, PhD, the current availability of advanced technology has made it possible to launch this bold new study. “This is the right time to take that technology forward,” he said. “We can now contemplate doing something that even a year ago would have been pretty hard to imagine.”
Physicians nowadays prescribe exercise routinely with particular attention to heart disease, weight control, and stress-related ailments. But, ultimately, the goal is to help them prescribe exercise on an individual basis. Such specificity would be based upon a clear understanding of the physical activity needed to assist each patient, rather than a one-size-fits-all approach.
The information gathered by all of the research sites involved in the consortium will be stored in a publicly accessible database that scientists can use to study almost every organ and tissue in the body.
Says 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: “To fully understand and subsequently transform clinical medicine’s use of physical activity for health management, a large-scale effort like this is imperative. Receiving this award is a testament to our outstanding faculty and our investment in genomics and systems biology research, which have positioned us to be able to contribute to this groundbreaking translational endeavor.”
Updated on Jun 30, 2022 | Featured, Research
Patients with more activity (the purple area throughout the image at right) in the brain’s center for stress and fear were more likely to have a heart attack or stroke, compared to patients with less activity (at left).
A Mount Sinai researcher has played a key role in tracing—for the first time—the mechanisms that link stress to cardiovascular events, like heart attack or stroke. Zahi A. Fayad, PhD, Director of the Translational and Molecular Imaging Institute at the Icahn School of Medicine at Mount Sinai, was co-senior author of a paper on the research, which was published January 12, 2017, in The Lancet. The work will be expanded in a five-year project, funded by a new $7 million grant from the National Institutes of Health (NIH).
The research found that people who had more activity in an area of the brain that regulates the body’s response to stress and fear, called the amygdala, were more likely to have a heart attack or stroke than those with less activity. The findings “provide more evidence of a heart-brain connection,” Dr. Fayad says. “It may seem obvious, but until now the evidence had not been shown. We had not seen the mechanistic link.”
The Lancet paper was based on two complementary studies. One study was led by the first author of the paper, Ahmed A. Tawakol, MD, Co-Director of the Cardiac MR PET CT Program at Massachusetts General Hospital in Boston. The study analyzed data from 293 people who from 2005 to 2008 underwent positron emission tomography–computed tomography (PET/CT) brain imaging, primarily for cancer screening, using a radiopharmaceutical called FDG that measures activity in the brain, vascular system, and bone marrow. Researchers found that over the next four years, 22 of the patients had cardiovascular events. In that group, many patients had initially shown a high level of activity in the amygdala and a greater amount of inflammation in the aorta, and in the bone marrow, where new blood cells are made. The latter two factors can contribute to atherosclerosis, the hardening and narrowing of the arteries, which increases the risk for heart disease. This pathway—from emotional stress to increased white blood cells to inflammation to atherosclerosis—has been identified in animals, but until now, not in humans.
Zahi A. Fayad, PhD
The second study, conducted by Dr. Fayad’s team at the Translational and Molecular Imaging Institute, examined 13 people who were being treated for post-traumatic stress disorder at Mount Sinai’s Mood and Anxiety Disorders Program. These patients completed a questionnaire about their perceived stress levels and underwent FDG-PET/MR scans. The team found that the patients’ stress levels were linked to increased activity in the amygdala, as well as increased inflammation in the blood vessels.
In the new project, Dr. Fayad—as overall principal investigator—will work with Dr. Tawakol; the leaders of the Mood and Anxiety Disorders Program, 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; and Program Director James Murrough, MD, Assistant Professor of Psychiatry, and Neuroscience; and others at Mount Sinai.
The project is seeking to study three groups of patients: 80 who are being treated for PTSD; 80 who are “resilient,” with past exposure to trauma but a low perceived level of stress; and 80 who have not been exposed to trauma. It will explore the possibility that alleviating stress could not just improve patients’ psychological sense of well-being, but also improve their physical atherosclerotic health. “In the future, chronic stress can be treated as a risk factor for cardiovascular disease,” Dr. Fayad says, “so we can screen for it and manage it like other risk factors.”
A patient with high activity in the amygdala also showed inflammation in the aorta (top right) and bone marrow in the spinal column (bottom right). Another patient with low activity in the amygdala showed little or no inflammation in the aorta (top left) and bone marrow (bottom left).
