Mayo Clinic Medical Science Blog – an eclectic collection of research- and research education-related stories: feature stories, mini news bites, learning opportunities, profiles and more from Mayo Clinic.
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Gastroenterologists agree that removing a colorectal polyp is an important step in preventing colon cancer, but one challenge has been excising polyps that are large, particularly those that are flat and more than an inch in diameter. A recently introduced minimally-invasive approach, called endoscopic mucosal resection, or EMR, facilitates the removal of large polyps without the need for surgery. “It’s highly effective in 98 percent of cases, but a limitation to EMR has been the issue of follow-up after the procedure,” says gastroenterologist Michael Wallace, M.D., on Mayo Clinic’s campus in Florida. Traditional testing after EMR has involved a biopsy or additional tissue removal six months later to affirm there’s no recurrence of the polyp at the same site.
In a study published in Gut, Dr. Wallace’s research team found that very effective follow-up to EMR can take place using an endoscope equipped with a zoom lens and a specialized light filter. The team compared the use of the advanced imaging technology, known as near-focus narrow-band imaging, with three other endoscopic lens-and-light combinations. The narrow-band light filter on the scope makes blood vessels stand out, enabling doctors to detect the vascularization characteristic of polyps and also to distinguish recurrent polyps from irregular scar tissue that occurs after EMR. “We found that the accuracy of the new technology to be 100 percent, predicting normal scar versus polyp. It eliminates the need for a biopsy or the removal of additional tissue,” Dr. Wallace says.
The technology offers the opportunity to reduce medical costs, he points out, but it’s also reassuring for patients. “We often see patients who were told after a screening colonoscopy that they needed life-changing colon surgery to remove a large polyp, that they would even need a colostomy bag,” he says. “This study underscores that large polyps can be removed effectively with EMR. Further, we now have a supplemental tool to know very accurately that we got all of the polyp and that it hasn’t recurred.”
The study was funded in part by the Joyce E. Baker Fund for Gastrointestinal Research at Mayo Clinic’s Florida campus. Other Mayo Clinic authors include Pujan Kandel, M.D., Eelco C. Brand, M.D., Joe Pelt, M.D., Colleen T. Ball, MS, Ernest P. Bouras, M.D., Victoria Gomez, M.D., Massimo Raimondo, M.D., Timothy A. Woodward, M.D. as well as Wei-Chung Chen, M.D. of Methodist Hospital, Houston, Texas.
It can be triggered by environmental or infectious agents and is characterized by an overactive immune response, involving clusters of white blood cells that aggregate in heart tissue. Those clusters can result in the need for a pacemaker, and may even lead to heart failure. But because it affects fewer than 10 out of every 100,000 people in North America and can have non-specific symptoms, cardiac sarcoidosis has been a particularly difficult disease to study.
A recent investigation led by Leslie T. Cooper, M.D., chair of cardiovascular medicine on Mayo Clinic’s campus in Florida, took a close look at the frequently used treatments for cardiac sarcoidosis and compared the long term results. Publishing in the European Journal of Heart Failure, the study involved collaborators at the University of Calgary and compared the effectiveness of the steroid prednisone, immunosuppressive agents other than prednisone, or no immunosuppressive treatment at all during the first months following diagnosis. Conducting one of the largest reviews of patient cases to date—a total of 91 patients—the team found none of the treatments provided greater long-term survival or prevention of heart failure.
“Regardless of therapy, there seems to be a high rate of heart failure in the five years following initial diagnosis,” says Dr. Cooper. “This study underscores the need for more research investigating new therapies for this unmet need.”
Such studies are underway at Mayo Clinic, which has established a cardiac sarcoidosis database to collect information about the disease. A research team in Rochester is developing new techniques to improve the diagnosis of cardiac sarcoidosis, including an innovative heart biopsy that can be added to magnetic resonance imaging (MRI). What’s more, the new Mayo Clinic Cardiac Sarcoidosis Clinic for patients has been established in Rochester.
Significantly, the study led by Dr. Cooper found that a small cohort of patients who had no symptoms, other than clusters in the heart, went on to develop heart failure in later years.
“Our study suggests the importance of long-term follow up with patients to monitor them for future events,” he says.
The international research team studying cardiac sarcoidosis included: Lynn A. Fussner, M.D.; David O. Hodge; Sanjay Kalra, M.D.; Eva M. Carmona, M.D., Ph.D.; and James P. Utz, M.D.; of Mayo Clinic; as well as Erin Karlstedt, M.D.; Nowell M. Fine, M.D.; and Debra L. Isaac, M.D.; of the University of Calgary. The study was funded by Mayo Clinic’s Department of Cardiovascular Medicine.
When a team of Mayo Clinic researchers discovered in 2011 the genetic repeat mutation known as c9orf72, the finding shed new light on amyotrophic lateral sclerosis (ALS). The mutation, which occurs as a short sequence of code repeated hundreds to thousands of times in the gene, is now known to appear in 40 percent of all familial cases of ALS and in nearly 10 percent of sporadic cases. It also occurs in 10 percent of the nearly 60,000 people with frontotemporal dementia (FTD), an early onset behavioral disease that sometimes overlaps with ALS.
“The identification of the gene was transformative for the field,” says Leonard Petrucelli, Ph.D., chair of neurosciences at Mayo Clinic’s campus in Florida. “It’s rare to find any gene that has potential to affect a lot of patients.”
Since that watershed discovery, reported in Neuron by the lab of neurogeneticist Rosa Rademakers, Ph.D., several neuroscience labs in Florida have launched studies to tease apart the effects of the c9 mutation and make sense of what causes neurodegeneration. Their c9 focus has paved the way to clinical trials for patients with ALS who have the mutation.
Here are some of the key steps along the research journey:
Based on the discovery of the c9 mutation, Dr. Petrucelli’s lab found that the gene results in an aberrant form of RNA, that’s capable of bypassing signals associated with normal protein synthesis. The repeat RNA leads to the accumulation of abnormal proteins. When they examined tissue samples from the Mayo Clinic brain bank, a vast resource directed by neuropathologist Dennis Dickson, M.D., the researchers recognized c9 repeat RNA and the abnormal proteins as unique pathologies. “These features occur only in those individuals who have the c9 mutation,” Dr. Petrucelli explains. That makes the molecules possible targets for future therapies. The team went on to develop a novel mouse model with the c9 gene mutation, a critical tool they reported in Science that can help them understand the disease and test emerging treatments.
Dr. Petrucelli’s lab has been investigating how the abnormal c9 proteins may cause ALS. In Nature Medicine, the team described how one such protein, known as poly(GR), accumulates in neurons and interferes with the creation of normal cellular proteins, causing the neurons to die. The lab’s recent studies have found that another protein has even more devastating effects on cells. These proteins now present potential targets for future drugs.
Along the way, other studies have also provided findings that can speed future clinical trials. Neuroscientist Tania Gendron, Ph.D., along with Dr. Petrucelli, and neurologist Kevin Boylan, M.D., found that another c9 protein, poly(GP), decreased when neurons were treated with drugs that target the abnormal repeat RNA. This finding, published in Science Translational Medicine, means that tracking poly(GP) protein levels in the spinal fluid of patients during a clinical trial can help determine whether or not a drug is effective at the cellular level, whether changing the dose might make a difference, or whether an effective drug is simply not reaching the appropriate brain cells. “Poly(GP) is the first pharmacodynamic marker for ALS in patients with the C9 mutation and may help make treatments available faster and rule out ineffective ones more quickly,” Dr. Gendron says.
Significantly, all these findings have set the stage for testing a potential treatment: antisense oligonucleotides, or ASOs, which target the repeat RNA. To date, ASOs have been used successfully to halt a devastating pediatric neurological disease, spinal muscle atrophy (SMA), also caused by a genetic repeat mutation. “It’s likely c9ALS is much more complicated than SMA as far as its pathological processes,” says neurologist Björn Oskarsson, M.D., “but we do believe that the c9 repeat expansion is the root cause of ALS in these patients and that reducing its effects could be powerful.”
ASOs, as a class of drugs, may someday be applicable to all ALS patients, but the basic science research has made it possible to develop clinical trials at select sites around the country for patients with the c9 version of the disease. “The work that’s taken place here has enabled this next hopeful step,” Dr. Oskarsson says.
Each year, more than one million women have biopsies that show non-cancerous changes in the breast, known as benign breast disease (BBD). Even though the changes may not require treatment, studies over the years at Mayo Clinic and elsewhere have found that not all cases of BBD are the same, and some will go on to develop breast cancer.
“The real challenge has been determining women’s individual risk for developing breast cancer in order to provide them with the best possible intervention,” says Mark Sherman, M.D., an epidemiologist and laboratory medicine and pathology researcher on Mayo Clinic’s campus in Florida.
Building on several decades of breast cancer research at Mayo Clinic, an interdisciplinary team aims to predict which women with BBD are at risk for breast cancer. The team, led by breast surgeon Amy Degnim, M.D., in Rochester, and Dr. Sherman, recently received a $3.1 million grant from the National Cancer Institute, a division of the National Institutes of Health to develop a breast cancer risk prediction model to help guide clinical care. The model will take into account demographic factors, as well as recent research about features of breast tissue that may heighten the risk for cancer.
Researchers at Mayo Clinic published the first report on a cohort of 9,000 women just over two decades ago, supporting previous studies that had stratified patients with BBD into high, medium and low risk categories. In the last 15 years, screening techniques have become more highly targeted, with the use of mammograms, magnetic resonance imaging (MRI), and radiologically-guided needle biopsies. They’re now catching more details in the breast changes. Just as significantly, new information has emerged about how characteristics of breast tissue, such as density, are relevant to risk. And recent studies have suggested when breast lobules, the ducts that make milk, don’t shrink as a woman ages, the risk for cancer increases.
Using information from more than 7,000 patients at Mayo Clinic in Rochester, the next-generation risk model will incorporate a wide range of risk factors, including demographics, samples from radiologically-guided needle biopsies, information about breast density, molecular biomarkers, and breast lobules. Partnering with a team from Karmanos Cancer Institute that has an established cohort of nearly 4,000 African American women, the study will also provide an understanding of ethnoracial breast cancer risk factors. The model will rely on big data and sophisticated machine learning techniques to generate risk predictions following a BBD diagnosis.
Ultimately, the model may provide women with highly individualized options. Those at high risk may consider preventive treatment, while those at low risk may avoid unnecessary tests.
“Even though we’ve been able to generalize predictions for patients, we know not everyone has the same degree of risk,” Dr. Sherman says. “Our goal is to achieve individualized risk prediction for a better targeted approach to care.”
Extracellular vesicles from cow’s milk may be a potential delivery vehicle for medical treatments for liver cancer.
Among cancers, liver tumors have been particularly hard for doctors to treat. The cancer cells tend to be hardy from the beginning and even undergo changes that make them more resistant to chemotherapies. What’s clear is that an effective treatment needs to reach the cancer cells, and not affect or damage the normal liver.
The trick, however, is getting drugs to the tumor. Researchers have been pinning hopes on getting drugs to cancer sites using the body’s own messaging system—extracellular vesicles, or EVs—tiny pouches released by cells that typically carry molecular messages from one cell to another.
In his lab, Tushar Patel, M.B., Ch.B., dean for research at Mayo Clinic’s Florida campus, investigates using these EVs as a way to deliver drugs and treatments into cancer cells. “EVs are released by many types of cells, and can even be found in most if not all bodily fluids,” he explains. “But in order to use them for cancer treatment, large quantities of EVs need to be available.”
Tushar Patel, M.B., Ch.B., discusses their lab’s work with some of his associates.
In a recent paper in Laboratory Investigation, Dr. Patel’s team showed that EVs could be obtained from milk, and then used to deliver treatments to the cells of hepatocellular carcinoma, a primary liver tumor that can be caused by cirrhosis. Cow’s milk—like human milk—has been known to contain EVs. Using EVs from milk has been an intriguing area of study, says Dr. Patel, and they can be easily isolated in large quantity.
Dr. Patel’s lab developed a process to isolate the EVs from casein protein in skim milk and use them for drug delivery. In laboratory tests, the team found that milk-derived EVs could be used to deliver chemotherapy as well as a new type of treatment based on using RNA molecules, known as an antisense nucleotide, into liver cancer cells, causing the cells to die. Researchers also found the treatment shrank tumors in mice. “The study suggested that the use of milk-derived nanovesicles may be a promising approach for delivering drugs to liver tumors,” he says.
“These results are very preliminary,” Dr. Patel says, adding that his lab is also investigating any potential harmful effects of using these milk-derived nanovesicles. “We want to know whether we can manipulate the proteins on the vesicles so that they will more directly recognize the tumor cells, even for a particular tumor type. Ultimately, we also want to know whether we can deliver this type of treatment orally and have the same kind of effect.” Future studies will aim to refine the use of milk-derived EVs for drug delivery with the eventual goal of taking these into clinical trials.
The research was funded in part through the Office of the Director, National Institutes of Health and the National Center for Advancing Translational Sciences, as well as through the Mayo Clinic Center for Regenerative Medicine.
Other researchers are Joseph George, Ph.D., currently of the Kanazawa Medical University, Japan, and Irene K. Yan of Mayo Clinic.
Neurologist Thomas Brott, M.D., vividly remembers when he first saw his research making a difference for patients. It was 1987, and for years, he’d been devastated to see patients suffering the immediate effects of a stroke: facial drooping, loss of language, and paralysis. A physician at the University of Cincinnati, he’d learned of a new clot-dissolving drug—tissue plasminogen activator, or t-PA—that seemed capable of restoring blood flow in a blocked carotid artery. When the National Institutes of Health requested research proposals, he organized investigators at several medical centers to test t-PA in patients with acute strokes.
He was on call at a participating hospital in Cincinnati when a patient suffering stroke paralysis received t-PA. The patient slowly regained motion as the drug took effect. “It was breathtaking,” he recalls.
Dr. Brott, who came to Mayo Clinic’s Jacksonville, Florida, campus as a clinician-researcher in 1998, has devoted his career to studying numerous methods of treating and preventing dangerous clots and brain bleeds. He’s led complex, multi-institutional clinical studies involving thousands of patients and has helped define some of the best treatment options for patients.
This year, Dr. Brott, the Eugene and Marcia Applebaum Professor of Neurosciences, was selected as the recipient of the 2017 Research Achievement Award from the American Heart Association. He received the honor during the AHA Scientific Sessions in Anaheim, California, “for his pivotal role in the development of life-saving interventions that have revolutionized treatment of acute ischemic stroke, with enormous consequent benefits dramatically reducing stroke death and disability in the world’s population,” the AHA reports. He’s the fifth Mayo Clinic researcher to receive the honor since its inception in 1953.
But research hasn’t always been a smooth ride, he acknowledges, and succeeding has involved perseverance and luck. In the early 1980s he became interested in complication rates of carotid endarterectomy, a surgical method of preventing stroke by removing plaque from a carotid artery. With no funding, he examined more than 500 patient charts at 12 area hospitals and found complications of the procedure alarmingly high.
Though he would eventually serve for eight years as the Director of Research on Mayo’s campus in Florida, at the time, he could not get his first paper published. He finagled an invitation to present his study at a meeting of the American Academy of Neurology. In a twist of fate, a producer from ABC News attending the meeting became interested in his findings and developed a feature on 20/20 and Nightline. Suddenly endarterectomy was in the news. Surgeons—including pre-eminent neurosurgeon Thoralf Sundt, M.D., at Mayo Clinic’s campus in Rochester—were interested in discussing the study with Dr. Brott. Ultimately, the study helped lead to randomized clinical trials defining the risks and benefits of carotid surgery.
Dr. Brott forged ahead, researching intracerebral hemorrhage and defining the dynamic changes in some patients’ brains immediately after a hemorrhagic stroke. Collaborating with other researchers, he investigated a drug for stroke. “It didn’t work, but I learned all the ins and outs of conducting a clinical trial,” he says. When the NIH requested a method to measure the severity of a patient’s stroke disability, Dr. Brott worked with a team to develop the National Institute of Health Stroke Scale (NIHSS), which became the standard examination scale for stroke patients worldwide.
Around the same time, he noticed a Science paper describing the use of t-PA to unblock coronary arteries and prevent heart attacks. He and others at an NIH meeting suggested a study using the drug to dissolve blood clots in arteries in the brain. NIH funded the study, and Dr. Brott’s team in Cincinnati enrolled most of the study’s patients. The introduction of the drug, now part of the standard of care for patients with small clots, was a key moment, says AHA President John Warner, M.D., “This triggered a major reorganization of stroke care delivery systems and the development of new tools to more reliably recognize its severity.”
During the last two decades at Mayo Clinic, Dr. Brott has focused on stroke prevention. He compared stenting—the insertion of wire mesh to widen a narrowed carotid artery—with endarterectomy in a randomized clinical trial involving more than 100 medical centers. Known as the Carotid Revascularization Endarterectomy vs. Stenting Trial, or CREST, the study he led evaluated more than 2,500 patients for ten years and found the two procedures to be equally safe and effective.
Dr. Brott is now the principal investigator for CREST II, for which he and neurologist James Meschia, M.D., received a National Institute of Neurological Disorders and Stroke grant of $39 million, one of the largest grants at Mayo Clinic. CREST II, a seven-year trial, is evaluating whether treatment with medicine (such as blood pressure drugs and statins) is as safe and effective as surgery or stenting in preventing a stroke. “Clinical research depends on good ideas, and I’ve learned it requires you to persevere, to be a bulldog. But you can’t do it without having great collaborators,” he says. “You have to be a bulldog who works with bulldogs.”
Researchers have known for several years that being overweight and having Type II diabetes can increase the risk of developing Alzheimer’s disease. But they’re now beginning to talk about another form of diabetes—Type III diabetes—that’s also associated with the neurodegenerative disease. This newly defined diabetes occurs when the neurons in the brain become unable to respond to insulin, essential for basic tasks including memory and learning. In fact, some researchers believe insulin deficiency is central to the cognitive decline of Alzheimer’s disease. Mayo Clinic’s campuses in Rochester and Jacksonville recently participated in a multi-institution clinical study, testing whether a new, insulin nasal spray can improve Alzheimer’s symptoms. The results of that study are still forthcoming.
But is all of this tied to the Alzheimer’s gene APOE? A new study from the lab of neuroscientist Guojun Bu, Ph.D., Mary Lowell Leary Professor of Medicine, on Mayo Clinic’s campus in Florida, found that the culprit is the variant of the Alzheimer’s gene known as APOE4. Publishing in Neuron, the team found APOE4, present in approximately 20 percent of the general population and over 50 percent of Alzheimer’s cases, is responsible for interrupting how insulin gets processed in the brain. Mice with the APOE4 gene showed insulin impairment, particularly in old age. What’s more, a high-fat diet could accelerate the process in middle-aged mice with the gene. “The gene and the peripheral insulin resistance, caused by the high-fat diet, together induced insulin resistance in the brain,” Dr. Bu says.
The team went on to describe how it all works in the neurons. They found that the APOE4 protein, produced by the gene, is able to bind more aggressively to insulin receptors on the surfaces of neurons than its normal counterpart, APOE3. As if playing a game of musical chairs, the APOE4 protein out-competes the normal protein and blocks the receptor. APOE4 goes on to do lasting damage to brain cells. After blocking the receptor, the sticky APOE4 protein begins to clump and become toxic. Further, once the protein enters the interior of the neuron, the clumps get trapped within the cell’s machinery, making the receptors themselves unable to get back to the surface of the neuron to do their work. The insulin signal processing gets increasingly more impaired, resulting in brain cells that are effectively starved.
“This study has furthered our understanding of the gene that’s the strongest genetic risk factor known for Alzheimer’s disease,” says Dr. Bu, who adds that ultimately, the finding may help personalize treatment for individual patients. “For instance, an insulin nasal spray or a similar treatment may be significantly more helpful for patients who don’t have the APOE4 gene. Patients who have the gene may need additional medications to help prevent cognitive decline.”
Na Zhao, M.D., Ph.D., and Chia-Chen Lieu, Ph.D., of the Department of Neuroscience on Mayo Clinic’s campus in Florida, are co-first authors of this study.
In addition, other researchers on the team are:
Alexandra J. Van Ingelgom, Mayo Clinic
Yuka A. Martens, Ph.D., Mayo Clinic
Cynthia Linares, Mayo Clinic
Joshua A. Knight, Mayo Clinic
Patrick M. Sullivan, Ph.D., Duke University School of Medicine