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News Article | April 7, 2016
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A team of researchers from Germany and the United States has successfully kept the heart of a pig continuously beating inside the body of a baboon for over two years. Now, experts believe the recent scientific breakthrough could lead the creation of genetically engineered organs that can be used to replace the damaged hearts of cardiac patients. In a study featured in the journal Nature Communications, scientists from the National Institutes of Health (NIH) made use of genetic engineering to produce pigs' hearts that are more compatible with the immune system of baboons. For years, organ transplants between different species (xenotransplantation) have been made complicated because of the tendency of the recipient's immune system to reject the new organ. However, by using organs from a genetically modified pig along with an immune-suppressing drug known as anti-CD40 antibody, the researchers were able to place pigs' hearts inside the bodies of five baboons. Instead of replacing the hearts of the baboons, the team simply added the new organs into their bodies and hooked them to the primates' circulatory system. This allowed the original baboon hearts to continue pumping blood. The researchers discovered that not only did the immune system of the baboons did not reject the pigs' hearts, but also the additional organs kept pumping inside the animals' bodies for an average of 945 days. This period was longer than any other time frames previously recorded by the team featuring pig-to-primate heart transplants in the past five years. The team believes that exposing the baboons to a regimen of the immune-suppressing drug played a key role in preventing the animals' immune system from rejecting the pigs' hearts while also allowing them to pump blood throughout their bodies well. Muhammad Mohiuddin, a cardiac transplant expert from the NIH's National Heart, Lung, and Blood Institute (NHLBI) and lead author of the study, pointed out that xenotransplantation was used to be considered merely some form of experimentation and that it carried no significant implications. However, with the results of the new study, Mohiuddin said that people are beginning to learn that cross-species organ transplants can actually work. The researchers chose pigs for the creation of laboratory-grown organs because of the animals' similarities, both physiologically and genetically, to humans. The growing demand for available organ donations has led researchers into developing ways to make xenotransplantations safer and more effective for patients. © 2016 Tech Times, All rights reserved. Do not reproduce without permission.

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Contrary to current clinical belief, regular caffeine consumption does not lead to extra heartbeats, which, while common, can lead in rare cases to heart-or stroke-related morbidity and mortality, according to UC San Francisco researchers. The study, which measured the chronic consumption of caffeinated products over a 12-month period, rather than acute consumption, appears in the January 2016 issue of the Journal of the American Heart Association. It is the largest to date to have evaluated dietary patterns in relation to extra heartbeats. "Clinical recommendations advising against the regular consumption of caffeinated products to prevent disturbances of the heart's cardiac rhythm should be reconsidered, as we may unnecessarily be discouraging consumption of items like chocolate, coffee and tea that might actually have cardiovascular benefits," said senior author Gregory Marcus, M.D., MAS, a UCSF Health cardiologist and director of clinical research in the UCSF Division of Cardiology. "Given our recent work demonstrating that extra heartbeats can be dangerous, this finding is especially relevant." Excessive premature atrial contractions (PACs) have been shown to result in atrial fibrillation, stroke and death, while excessive premature ventricular contractions (PVCs) have been shown to result in increased heart failure, coronary artery disease and death. Both abnormalities have been tied to caffeine consumption through studies and trials, but these studies were performed several decades ago and did not use PACs and PVCs as a primary outcome. Nonetheless, the American College of Cardiology/American Heart Association guidelines on the management of PVCs state that if a patient's history is consistent with premature extra beats, potential exacerbating factors such as caffeine, alcohol and nicotine should be eliminated. Other online medical resources for clinicians offer similar recommendations. Recent growing evidence indicates the potential cardiovascular benefits of several common caffeinated products such as coffee, chocolate and tea. The result is clinician uncertainty in counseling patients on consumption of these products, with patients possibly reducing their intake to avoid presumed cardiac issues. In their study, Marcus and his colleagues analyzed 1,388 randomly selected participants from the National Heart, Lung, and Blood Institute (NHLBI) Cardiovascular Health Study database of nearly 6,000 patients, excluding those with persistent extra heartbeats. They were given a baseline food frequency assessment and 24-hour ambulatory electrocardiography monitoring. Frequencies of habitual coffee, tea and chocolate consumption were determined through a survey. Of the total participants, 840 (61 percent) consumed more than one caffeinated product daily. The researchers found no differences in the number of PACs or PVCs per hour across levels of coffee, tea and chocolate consumption. More frequent consumption of these products was not associated with extra heartbeats. "This was the first community-based sample to look at the impact of caffeine on extra heartbeats, as previous studies looked at people with known arrhythmias," said lead author Shalini Dixit, BA, a fourth-year medical student at UCSF. "Whether acute consumption of these caffeinated products affects extra heartbeats requires further study."

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A new Northwestern Medicine study has pinpointed thousands of genetic pathways an internal body clock takes to dictate how and when our pancreas must produce insulin and control blood sugar, findings that could eventually lead to new therapies for children and adults with diabetes. The body’s circadian clocks coordinate behaviors like eating and sleeping, as well as physiological activity like metabolism, with the Earth’s 24-hour light-dark cycle. There’s a master clock in the brain, as well as peripheral clocks located in individual organs. When genetics, environment or behavior disrupt the synchrony of these clocks, metabolic disorders can develop. In a previous publication in Nature, Northwestern Medicine investigators showed that a circadian clock in the pancreas is essential for regulating insulin secretion and balancing blood sugar levels in mice. The scientists demonstrated that knocking out clock genes led to obesity and type 2 diabetes, but they still had much to learn if they wanted to manipulate clock action to treat the conditions. “We knew that the pancreas didn’t work if we removed these clock genes, but we didn’t know how the genes were affecting the normal function of the pancreas,” said principal investigator Dr. Joe Bass, chief of endocrinology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. Clock genes are responsible for producing transcription factors, special proteins that help tell a cell how to function. In the new study, published Nov. 6 in Science, Bass’s laboratory revealed thousands of genes in the pancreas that the clock’s transcription factors control in rhythm with the planet’s daily rotation from light to dark. “We established a new gene map that shows how the entire repertoire of factors produced in the pancreas maintain and anticipate daily changes in the external environment,” Bass said. “These factors are all tied to the rotation of the Earth -- to the timekeeping mechanism that has evolved to control when we sleep, wake up, eat and store nutrients each day.” Bass’s team focused on cells in the pancreas called beta cells, which secrete insulin into the blood stream to help the body absorb glucose -- sugar -- to use for energy. Using genome-wide sequencing technology on beta cells with both intact and disrupted clock gene function, the scientists were able to lay out the map of transcription factors and genes. In ongoing research, Bass’s group continues to study how the body’s circadian clocks interact and how their rhythm is thrown off -- not just in diabetes, but also during the normal aging process and from day-to-day conditions like jetlag, stress or dietary changes. “This study reinforces the idea that clocks operating in cells are fundamental to health,” Bass said. “They represent an important untapped target for improving the functions of cells in the pancreas.” Bass is also the Charles F. Kettering Professorship of Medicine at Feinberg. Other Northwestern authors include Dr. Grant Barish, Mark Perelis, Biliana Marcheva, Kathryn Ramsey, Clara Bien Peek, Hee-kyung Hong, Matthew Schipma, Dr. Akihiko Taguchi, Dr. Wenyu Huang, Chiaki Omura and Amanda Allred. This study was supported by National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH National Institute on Aging , the Chicago Biomedical Consortium , Juvenile Diabetes Research Foundation , University of Chicago Diabetes Research and Training Center 5; NIDDK T32 ; National Heart, Lung, and Blood Institute T32and Defense Advanced Research Projects Agency.

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Drugs delivered by nanoparticles hold promise for targeted treatment of many diseases, including cancer. However, the particles have to be injected into patients, which has limited their usefulness so far. Now, researchers from MIT and Brigham and Women’s Hospital (BWH) have developed a new type of nanoparticle that can be delivered orally and absorbed through the digestive tract, allowing patients to simply take a pill instead of receiving injections. In a paper appearing in the Nov. 27 online edition of Science Translational Medicine, the researchers used the particles to demonstrate oral delivery of insulin in mice, but they say the particles could be used to carry any kind of drug that can be encapsulated in a nanoparticle. The new nanoparticles are coated with antibodies that act as a key to unlock receptors found on the surfaces of cells that line the intestine, allowing the nanoparticles to break through the intestinal walls and enter the bloodstream. This type of drug delivery could be especially useful in developing new treatments for conditions such as high cholesterol or arthritis. Patients with those diseases would be much more likely to take pills regularly than to make frequent visits to a doctor’s office to receive nanoparticle injections, say the researchers. “If you were a patient and you had a choice, there’s just no question: Patients would always prefer drugs they can take orally,” says Robert Langer, the David H. Koch Institute Professor at MIT, a member of MIT’s Koch Institute for Integrative Cancer Research, and an author of the Science Translational Medicine paper. Lead authors of the paper are former MIT grad student Eric Pridgen and former BWH postdoc Frank Alexis, and the senior author is Omid Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at BWH. Other authors are Timothy Kuo, a gastroenterologist at BWH; Etgar Levy-Nissenbaum, a former BWH postdoc; Rohit Karnik, an MIT associate professor of mechanical engineering; and Richard Blumberg, co-director of BWH’s Biomedical Research Institute. Several types of nanoparticles carrying chemotherapy drugs or short interfering RNA, which can turn off selected genes, are now in clinical trials to treat cancer and other diseases. These particles exploit the fact that tumors and other diseased tissues are surrounded by leaky blood vessels. After the particles are intravenously injected into patients, they seep through those leaky vessels and release their payload at the tumor site. For nanoparticles to be taken orally, they need to be able to get through the intestinal lining, which is made of a layer of epithelial cells that join together to form impenetrable barriers called tight junctions. “The key challenge is how to make a nanoparticle get through this barrier of cells. Whenever cells want to form a barrier, they make these attachments from cell to cell, analogous to a brick wall where the bricks are the cells and the mortar is the attachments, and nothing can penetrate that wall,” Farokhzad says. Researchers have previously tried to break through this wall by temporarily disrupting the tight junctions, allowing drugs through. However, this approach can have unwanted side effects because when the barriers are broken, harmful bacteria can also get through. To build nanoparticles that can selectively break through the barrier, the researchers took advantage of previous work that revealed how babies absorb antibodies from their mothers’ milk, boosting their own immune defenses. Those antibodies grab onto a cell surface receptor called the FcRN, granting them access through the cells of the intestinal lining into adjacent blood vessels. The researchers coated their nanoparticles with Fc proteins — the part of the antibody that binds to the FcRN receptor, which is also found in adult intestinal cells. The nanoparticles, made of a biocompatible polymer called PLA-PEG, can carry a large drug payload, such as insulin, in their core. After the particles are ingested, the Fc proteins grab on to the FcRN in the intestinal lining and gain entry, bringing the entire nanoparticle along with them. “It illustrates a very general concept where we can use these receptors to traffic nanoparticles that could contain pretty much anything. Any molecule that has difficulty crossing the barrier could be loaded in the nanoparticle and trafficked across,” Karnik says. The researchers’ discovery of how this type of particle can penetrate cells is a key step to achieving oral nanoparticle delivery, says Edith Mathiowitz, a professor of molecular pharmacology, physiology, and biotechnology at Brown University. “Before we understand how these particles are being transported, we can’t develop any delivery system,” says Mathiowitz, who was not part of the research team. In this study, the researchers demonstrated oral delivery of insulin in mice. Nanoparticles coated with Fc proteins reached the bloodstream 11-fold more efficiently than equivalent nanoparticles without the coating. Furthermore, the amount of insulin delivered was large enough to lower the mice’s blood sugar levels. The researchers now hope to apply the same principles to designing nanoparticles that can cross other barriers, such as the blood-brain barrier, which prevents many drugs from reaching the brain. “If you can penetrate the mucosa in the intestine, maybe next you can penetrate the mucosa in the lungs, maybe the blood-brain barrier, maybe the placental barrier,” Farokhzad says. They are also working on optimizing drug release from the nanoparticles in preparation for further animal tests, either with insulin or other drugs. The research was funded by a Koch-Prostate Cancer Foundation Award in Nanotherapeutics; the National Cancer Institute Center of Cancer Nanotechnology Excellence at MIT-Harvard; a National Heart, Lung, and Blood Institute Program of Excellence in Nanotechnology Award; and the National Institute of Biomedical Imaging and Bioengineering.

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People who drink sugary beverages, such as soda or fruit juice, daily tend to gain a type of body fat associated with diabetes and heart disease, a new study finds. Researchers looked at about 1,000 middle-age people over a six-year period and found that those who drank sugar-sweetened beverages tended to have more "deep," or visceral, fat. This type of fat wraps around the internal organs, including the liver, pancreas and intestines; affects hormone function; and may play a role in insulin resistance, the researchers said. Previous research has linked sweet drinks with other health risks. "There is evidence linking sugar-sweetened beverages with cardiovascular disease and type 2 diabetes," Dr. Caroline Fox, lead author of the new study and a former investigator with the Framingham Heart Study of the National Heart, Lung, and Blood Institute, said in a statement. "Our message to consumers is to follow the current dietary guidelines and to be mindful of how much sugar-sweetened beverages they drink." [8 Tips for Fighting Sugar Cravings] In the new study, the researchers gave a dietary survey to 1,003 people, nearly half of them women, whose average age was 45. The participants answered a variety of questions, including how often they consumed drinks with added sugar — largely with sucrose or high fructose corn syrup — because these beverages are the largest contributors of added sugar intake in the United States, according to the study, published online today (Jan. 11) in the journal Circulation. All of the participants underwent computer tomography (CT) scans at the beginning and end of the study, allowing the researchers to measure changes in visceral fat. After controlling for several factors that can affect people's amount of visceral fat — including their age, gender, physical activity level and body mass index (BMI) — the researchers found that over the course of the study, the participants who never drank sugar-sweetened beverages and the participants who drank them only occasionally gained the least amount of body fat: about 40 cubic inches each (or 658 cubic centimeters and 649 cubic centimeters, respectively), on average. Those who drank the beverages frequently (at least once a week, but less than daily) gained 43 cubic inches (707 cubic cm) of visceral fat, on average. Daily sugary-beverage drinkers gained the most visceral fat — 52 more cubic inches (852 cubic cm), on average — at the end of the study than they had at the study's start, the researchers found. Overall, people who drank sugary drinks were more likely to be male, younger, smokers, engaged in slightly more physical activity and less likely to have diabetes, the researchers noted. Interestingly, there was no association between diet soda and visceral-fat increase, likely because diet soda tends to be low in calories and sugar, the researchers said. However, they noted that the diet-soda drinkers in the study were less likely to be engaged in physical activity, had higher BMIs and had a higher prevalence of diabetes than those in the study who didn't drink diet soda. Exactly how sweet drinks may get converted into visceral fat is unknown, the researchers said. But the results clearly show that "individuals who consumed higher amounts of sugar-sweetened beverages gained more visceral fat over time," Fox told Live Science. Perhaps the high amounts of sugar in these drinks contributes to insulin resistance, or a reduced ability of body cells to take up sugar from the blood, and this contributes to the development of visceral fat, said study co-leader Dr. Jiantao Ma, a postdoctoral fellow at the National Institutes of Health. Insulin resistance can increase people's risk for type 2 diabetes and heart disease, he said. Visceral fat is also associated with other maladies. Being pear-shaped because of belly fat is linked to an increased risk of kidney disease. Moreover, women who have increased belly fat are at increased risk of developing osteoporosis, research finds. The American Heart Association recommends that women consume no more than 100 calories per day from added sugars, including those found in sweetened drinks, and that men consume no more than 150 calories per day from added sugars.

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