Newswise — Children with differences of sex development (DSD) are born with reproductive organs that are not typically male or female. They may face infertility from abnormal development of testes or ovaries, and in some patients these organs are surgically removed to prevent an increased risk of germ cell cancer. With advancing techniques, however, children with DSD may be able to preserve their fertility for the future. This potential also presents important ethical issues, which are examined in an article published in the Journal of the Endocrine Society. “Our earlier research suggests that in children with DSD, we might be more successful in preserving fertility at younger ages,” says senior author Courtney Finlayson, MD, from Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago. “This poses a dilemma in terms of the ideal timing for surgical removal of testes or ovaries for patients who need it. If we wait until the age of majority, when the patient can give consent, we might miss the opportunity for fertility preservation. And yet we might want to delay the surgery since we must also take into account a person’s sense of self as a man or a woman and autonomous decision making. It is a delicate balance.” Fertility preservation techniques involve preserving at very low temperatures the mature or immature tissue from the testes or ovaries. The procedure is still experimental for pre-pubertal patients, since it relies on the development of technologies to mature germ cells in the lab. Given the uncertainty of success, there is concern that these techniques can lead to false hope for patients and parents. Cost and insurance coverage are additional concerns. Fertility preservation is expensive, ranging from thousands to tens of thousands of dollars. It is rarely covered by insurance and is mostly considered an elective procedure. “We can make an argument that fertility preservation in children with DSD should be covered by insurance since DSD treatment can cause infertility, which can result in serious psychological distress,” says Finlayson, an endocrinologist with the Gender and Sex Development Program at Lurie Children’s and an Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “Lack of insurance coverage significantly limits access to preserving future fertility in these children.” Because many DSD are genetic conditions that can be inherited, there is also concern about transmission to offspring. Some ethicists argue that it is irresponsible to knowingly have children with a medical condition or disability. On the other hand, advocates assert that people with disabilities can lead happy, productive lives. Furthermore, many with DSD object to their condition being referred to as a disorder or disease. In either case, adults concerned about having children with the same condition could benefit from pre-implantation genetic screening of embryos. Another ethical consideration revolves around gender dysphoria, or the distress that some individuals with DSD experience when their early sex assignment does not match their eventual gender identity. For example, youth initially assigned male but identifying as female might feel emotional distress at providing sperm for fertility preservation. Also, high-dose estrogen or testosterone required for fertility preservation can cause irreversible physical changes that are inconsistent with gender identity. “There are no easy answers to any of these ethical concerns,” says Finlayson. “Fertility-related care for children with DSD is in its infancy. We must carefully consider the unique ethical issues that fertility preservation presents in this population.” Research at Ann & Robert H. Lurie Children’s Hospital of Chicago is conducted through the Stanley Manne Children’s Research Institute. The Manne Research Institute is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children’s is ranked as one of the nation’s top children’s hospitals in the U.S.News & World Report. It is the pediatric training ground for Northwestern University Feinberg School of Medicine. Last year, the hospital served more than 198,000 children from 50 states and 51 countries. SEE ORIGINAL STUDY
Newswise — A genetic test that helps doctors determine how best to treat breast cancer—and whether chemotherapy is likely to help—is significantly more likely to be administered to white women than blacks or Hispanics, a Yale study has found. Women of color have less access to the Oncotype Dx test, mammography and radiation treatments. The test, called Oncotype Dx (ODx), uses gene expression to gauge how early-stage breast cancer is affecting patients’ gene activity. It uses the information to determine how likely cancer recurrence would be, and physicians and their patients can use that knowledge to decide how to proceed with treatment. Yale researchers retrospectively analyzed a group of more than 8,000 Connecticut women who were diagnosed with hormone receptor positive breast cancer between 2011 and 2013, and found “significant racial and ethnic disparities in use of this new gene test,” said study leader Dr. Cary Gross, a member of Yale Cancer Center and professor of medicine and epidemiology at Yale School of Medicine.
Newswise — GAINESVILLE, Fla. --- A glass of milk packs a nutritious punch, a reminder of the importance of dairy in our diets as we enter National Dairy Month, a University of Florida nutrition expert said. “Basically, cow’s milk helps to meet nutrient needs, and some research suggests it may help to protect against some of the major chronic diseases,” said Gail Kauwell, a professor in food science and human nutrition. Dairy food nutrients play many important roles in maintaining good health, so Kauwell encourages milk as part of a healthy eating pattern. Some key nutrients in milk include calcium, vitamins D and B12, potassium and protein. These nutrients build strong bones and teeth, maintain and improve bone mass, make red blood cells, synthesize DNA and maintain healthy blood pressure, said Kauwell, a faculty member at the UF Institute of Food and Agricultural Sciences. For example, studies support an association between higher dairy food intake and lower risk for type 2 diabetes, said Kauwell, although she cautions that these studies do not prove cause and effect. All sorts of “milk” fills the grocery store dairy case. So how do consumers distinguish between them? Further, what do you do if you cannot consume a certain type of dairy product? Kauwell explained that several of the key vitamins and minerals naturally present in cow’s milk are only present in soy, almond, rice and coconut beverages if they are added to the product. And when it comes to protein, only soy beverages provide an amount equal to that of cow’s milk. People who are lactose intolerant may be able to drink small amounts of milk without experiencing any symptoms but may prefer to drink lactose-free milk or a fortified soy beverage. On the other hand, some people cannot drink cow’s milk because of a food allergy. Those with a food allergy to milk, and those practicing a vegetarian or vegan diet also may choose to drink a fortified soy beverage, said Kaley Mialki, a UF/IFAS graduate and registered dietitian. “If individuals are watching their weight, switching from full-fat milk, cheese and yogurt to low-fat or fat-free milk products can reduce calorie and fat consumption but still allow for intake of other important nutrients like protein, vitamins and minerals,” Mialki said. -30- The mission of the University of Florida Institute of Food and Agricultural Sciences is to develop knowledge relevant to agricultural, human and natural resources and to make that knowledge available to sustain and enhance the quality of human life. With more than a dozen research facilities, 67 county Extension offices, and award-winning students and faculty in the UF College of Agricultural and Life Sciences, UF/IFAS works to bring science-based solutions to the state’s agricultural and natural resources industries, and all Florida residents. Visit the UF/IFAS web site at ifas.ufl.edu and follow us on social media at @UF_IFAS.
Newswise — ST. LOUIS – Children with complex medical conditions and those who are just in need of a regular teeth cleaning will soon have a new program devoted to their care. Saint Louis University’s Center for Advanced Dental Education (CADE) will begin a pediatric dentistry residency program on July 1, 2017. The program, six years in the making, received initial accreditation from the Commission on Dental Accreditation in February. SLU’s pediatric program is the only residency program of its kind in eastern Missouri or southern Illinois. The two-year graduate program provides dentists an opportunity to study and receive clinical experience in treating children. Residents learn advanced diagnostic and surgical procedures, along with oral pathology, child-related pharmacology, radiology, child development, management of oral/facial trauma, care for patients with special needs, conscious sedation and general anesthesia. CADE currently offers specialty training in endodontics (root canals), orthodontics (braces) and periodontics (treatment of gum disease and implants). “We are really excited to get this program started – it will be tremendous for the region,” said John Hatton, DMD, executive director of CADE. “There are so many children in the area that have nowhere to go for their dental needs.” Hatton said early intervention is important in dental health. “Through CADE’s other programs, a person can have a tooth extracted instead of a root canal, not replace a missing tooth with an implant and function without braces,” Hatton said. “And now, with our new pediatric dentistry program, we can intervene early to improve a child’s oral health, which makes a difference for the rest of their life.” SLU’s program will admit three students in its first year and another three the following year. Applicants must have a strong academic background and clinical skills, as well as a passion for working with children. “Pediatric dentistry is more than just being child-friendly,” said Dan Stoeckel D.D.S., MS, pediatric dentistry graduate program director. “You have to enjoy working with kids and also work within the growth and development of a child’s mouth. Children can have extensive needs that are not the same as those of an adult patient.” Residents admitted to the program will serve patients in a clinical setting at CADE and, when necessary, perform dental care under general anesthesia at SSM Health Cardinal Glennon Children’s Hospital. “We will treat the patients of general pediatrics and the specialty clinics of SSM Health Cardinal Glennon Children’s Hospital, as well as provide a dental home for children from birth to age 12,” Stoeckel said. SLUCare physicians at Danis Pediatric Center at SSM Health Cardinal Glennon Children’s Hospital will directly refer low-income patients to the pediatric dental clinic for regular cleanings and checkups. “Small steps to improve oral hygiene can have a big impact on overall health,” Stoeckel said. “We will work with our patients to create a personalized preventative care plan for oral health.” The clinic will also care for children with additional medical needs, ranging from those with blood disorders and cancer patients, to patients who have autism and Down syndrome. “Residents will see patients with needs ranging from basic cleanings to complicated restorative dentistry,” Stoeckel said. “They also will learn how to manage patients that come into the clinic with a high level of anxiety.” The residents also will provide on-call emergency dentistry coverage at Cardinal Glennon. In February 2016, the Glennon Guild donated $50,000 to support the renovation and equipping of the Pediatric Dental clinic at the Center for Advanced Dental Education. The clinic opened Nov. 30. “I think once we have the residents on board we will be able to see 5,500 patients a year, with 1,800 of those being unique visitors,” Stoeckel said. Appointments are now being accepted for late summer at 314-977-PEDO (7336). All forms of Missouri and Illinois Medicaid are accepted. The Center for Advanced Dental Education’s mission is to achieve the highest level of excellence in scholarship and patient care while educating dentists in the specialties of orthodontics (tooth straightening), endodontics (root canal treatment), periodontics (gum disease therapy) and pediatric dentistry. The center aims to serve its students, the profession of dentistry, the community of St. Louis, and the communities in which the graduates of CADE will practice their dental specialty.
Newswise — Texas communities facing a rural hospital closure should not solely concentrate on whether or not to close a hospital, but instead focus on the available health resources in the surrounding area. That’s one of the findings of a new report by the Texas A&M Rural and Community Health Institute (RCHI) that examined rural hospital closures and looks at new solutions for rural healthcare concerns. The Episcopal Health Foundation (EHF) sponsored the report. The report found that options like expanding telemedicine, converting a former hospital into a freestanding emergency room, or establishing new rural health clinics are some of the many successful healthcare alternatives available to communities at risk of losing a traditional rural hospital. See the complete report: http://bit.ly/2qB7cpp “We still have an American concept that every town should have a hospital,” said Nancy Dickey, MD, RCHI’s executive director, president emeritus of the Texas A&M Health Science Center and co-author of the report. “But the growing reality is that it’s not cost effective. The good news is there’s a menu of alternatives that can help optimize healthcare for a rural community, not shut down healthcare in that community.” More than 3 million Texans live in rural areas and the report clearly shows the growing health crisis they face. Rural Texans are more likely to be uninsured, have lower incomes, and higher rates of death from heart disease and stroke. Researchers found the health gap between urban and rural areas is widening and the number of physicians working in rural areas continues to fall. They point to statistics showing that 158 counties in Texas (with a combined population of 1.9 million) do not have a general surgeon and 147 counties (1.8 million people) don’t have an obstetrician/gynecologist. In 35 Texas counties, there is no physician at all. The report also found that since 2010, more than 15 percent of the rural hospitals that have closed across the U.S. are in Texas. “Policy makers, elected officials and communities themselves need to better understand the health challenges facing rural areas,” said Elena Marks, EHF’s president and CEO. “This report shows that the question to ask isn’t only whether to close or not close a rural hospital. It stresses the importance of regional partnerships and collaborations that can help develop a system of accessible health services that meet the unique needs of each community.” In the report, researchers examined rural hospital closures across the country and interviewed former leaders of shuttered hospitals. While the report found that most rural hospitals in Texas closed due to financial difficulties and lack of patient volume, it also found that there are often available healthcare delivery resources within a radius of 20 to 30 miles from the closed facility. “It’s not about miles, it’s about minutes,” Dickey said. “We need to have a policy discussion at the state and national level to determine what is an acceptable timeframe to reach care. Geography confirms that every community is a little different.” Researchers suggest communities facing a hospital closure first ask community members where they currently go for healthcare services. Then, leaders can use that information to create a tool to help at-risk hospitals search for alternatives and develop area partnerships that create an inventory of resources without duplicating care. “There are opportunities for these communities to reframe the health conversation and go beyond ‘Why are they closing my hospital?’” Dickey said. “There are a variety of solutions and if large hospital systems and rural hospitals can work together, they can find patient-centered answers for at-risk communities.” About Texas A&M Health Science Center Texas A&M Health Science Center is Transforming Health through innovative research, education and service in dentistry, medicine, nursing, pharmacy, public health and medical sciences. As an independent state agency and academic unit of Texas A&M University, the health science center serves the state through campuses in Bryan-College Station, Dallas, Temple, Houston, Round Rock, Kingsville, Corpus Christi and McAllen. Learn more at https://vitalrecord.tamhsc.edu/ or follow @TAMHSC on Twitter.
Newswise — Researchers at Johns Hopkins Medicine report new evidence that immune cells infected with a latent form of human immunodeficiency virus (HIV) are able to proliferate, replenishing the reservoir of virus that is resistant to antiretroviral drug therapy. Although HIV can be controlled with therapy in most cases, the proliferation of such reservoir cells pose a persistent barrier to developing a cure for HIV, researchers say. “We knew before that the reservoir is very long lived,” says Robert Siliciano, M.D., Ph.D., professor of medicine at the Johns Hopkins University School of Medicine, “but what we didn’t know was how the reservoir was maintained. Now it is clear that these cells aren’t just sitting there but are dividing and replenishing themselves.” A report on the new research, published March 24 in the Journal of Experimental Medicine, says resting CD4+ T cells not only make up the latent reservoir of HIV in those infected, but also have the potential to reactivate the production of active virus throughout the body. In the study, Siliciano and his team collected latently infected HIV cells from the blood of 12 patients with HIV on long-term antiretroviral therapy. After growing the CD4+ T cells in the laboratory, the investigators exposed them to four rounds of chemicals designed to stimulate cell division and proliferation. After each round of stimulation, the cell population was split into two separate groups and allowed to grow, one serving as a control and the other used to repeat the process. Following each stimulation, the researchers also measured whether the cells were releasing HIV. Previously, Siliciano explains, researchers suspected that such cells could not proliferate without releasing the active form of HIV. Although some cells did release HIV during the first stimulation, the subsequent stimulations of each cell line also released more virus, suggesting that some of the latently infected cells divided without releasing the infectious virus and maintained the ability to do so in subsequent stimulations. The researchers then sequenced the genomes of the viruses. They speculated that if the viruses in subsequent stimulations from each patient were genetically identical, that would tell them the HIV they detected originated from cell division, rather than from independent infections because of HIV’s high genetic mutation rate. “When you sequence HIV from a patient, you typically get a huge variety of HIV viruses that are genetically different. Looking at the viruses we grew out, there was much less diversity. In fact, the sequences were mostly identical throughout the series of stimulations. We think that strongly suggests that what we are seeing is a single cell proliferating and copying the HIV DNA along with it,” Siliciano says. Siliciano’s team found that these kinds of viral copies were so common they could find multiple cells carrying the same variant of HIV in a single blood sample. “For this to be possible, the reservoir must be mostly composed of these cellular clones.” In the future, Siliciano and his team say they will search for specific factors that cause these cells to proliferate and to develop new techniques that allow them to study whether the location of the HIV genome in the cell’s DNA affects this process. More than 1.2 million people in the U.S. are living with HIV and one in eight of them are unaware that they are infected, according to the Centers for Disease Control and Prevention. Stigma and discrimination around HIV is still a major challenge to reaching and treating infected people, so the CDC estimates that only half of infected people have their virus under control with consistent treatment. However, the number of new HIV cases has fallen significantly since the 1990s and with improved awareness and improved treatments, the life expectancy of people infected with HIV is close to that of the general population. “Treatments now are so good,” Siliciano says, “that if we are able to eliminate the reservoir, we could cure HIV.” Other researchers involved in this study include Nina Hosmane, Kyungyoon Kwon, Katherine Bruner, Adam Capoferri, Subul Beg, Ya-Chi Ho and Janet Siliciano of the Johns Hopkins University School of Medicine, Daniel Rosenbloom of the Columbia University Medical Center and Brandon Keele of the Fredrick National Laboratory for Cancer Research. This work was supported by the National Institute of Allergy and Infectious Diseases Extramural Activities Martin Delaney CARE and DARE Collaboratories (AI096113 and 1UI9AI096109), an ARCHE Collaborative Research Grant from the Foundation for AIDS Research (amfAR 108165-50-RGRL), The Johns Hopkins Center for AIDS Research (P30AI094189), the National Institutes of Health (43222), the Howard Hughes Medical Institute, the Bill and Melinda Gates Foundation, and the National Cancer Institute and National Institutes of Health (HHSN261200800001E).
Newswise — With a number of high-profile cases of prescription medication prices suddenly skyrocketing, people naturally start to wonder if perhaps some government control over the price of drugs might be a good idea. However, due to the high risk and high cost of developing new drugs, it’s possible that capping the amount of money that can be made from them would suppress development of new therapeutics. “If we have price controls, on the one hand, it seems like a good thing for the consumer,” said Mansoor A. Khan, RPh, PhD, professor and vice dean of the Texas A&M Irma Lerma Rangel College of Pharmacy College Station campus, “but, on the other hand, why would companies spend in excess of two billion dollars and wait 10 or more years to develop a drug if they can’t make a huge profit? That’s the balance we need to strike.” Adding to the risk is the possibility that drugs might be pulled from the market before they can make any money at all, and as many as 80 percent of the drugs that are sold don’t recover the amount of money spent on their development completely, according to Khan. At the same time, some blockbuster drugs manage to make billions of dollars, and that helps encourage drug companies to continue to create new medications. “It’s an extremely high-risk, but highly profitable business,” he said. Khan sees the approval of generics and competition in the market as being key to driving down costs. “We have a very good system in place in the United States to allow generic drugs after a certain number of years of exclusivity,” said Khan, who was director of the Division of Product Quality Research at the Food and Drug Administration (FDA) before joining Texas A&M. “About 88 percent of prescriptions are generic, and those manufacturers are able to copy the formulas of the original drug and avoid the extensive safety and efficacy clinical trials in patient populations, which means the medication becomes very inexpensive.” However, that’s only if the system works properly, and it doesn’t always. “Some brand products have been around a long time—and their exclusivity has long since expired—but there are still no generics,” Khan said. “That’s something the FDA needs to deal with more effectively.” One reason for the lack of generics is that sometimes a brand name drug company will file a citizen petition with the FDA, saying that manufacture of the drug is risky and complicated and that if generics are allowed, they may cause problems. “Generic approvals get delayed because of these petitions, and the FDA may ask the generic company to do additional testing or need extended multiple cycle of responses,” Khan said. These citizen petitions and response cycle times have the potential to delay timely access to generic medications. Generally, generics don’t have to undergo a lot of clinical pharmacodynamics studies or animal safety testing; they simply must show that their product has pharmaceutical equivalence and bioequivalence with the original drug—which provide an indication that it is also therapeutically equivalent. However, when the drug is something that is not absorbed into the body in sufficient quantities to be detected in the blood, bioequivalence can be difficult to prove. This is generally the case for locally acting antibiotics and anti-inflammatory drugs in the gastrointestinal tract, products topically applied to the skin or ocular products because their concentrations are not significant enough in the blood to measure and quantitate. Regulations do exist to do bioequivalence by in vitro laboratory studies, but there are not many published and peer-reviewed studies to show and validate what those in vitro studies are. Still, there are ways to approach the problem if the brand name drug company is insisting on further testing. “The regulations do provide a window, it’s just that a scientific determination needs to be made,” Khan said. “If the generic is made exactly the same as the brand, then you can test its stability and release in the different environments that exist in the human body, and if the release of the drug is the same or very similar as the brand, then we propose that it is very likely they will behave similarly in a human being.” A precedence of this approval by in vitro procedures without clinical bioequivalence studies is provided by the approval of locally acting vancomycin antibiotic capsules. Additionally, many generic products are made outside the United States. Inspections of those facilities are difficult and more complicated than inspection of domestic facilities. “Foreign facility inspections need to be streamlined and should be on par with the frequency of domestic inspections,” Khan said. “If they are not streamlined to ensure a consistently good quality generic product quality, we may see more problems of drug shortages with unexpected post-market failures.” Khan sees bringing the industry back to the United States as a required remedy, but says we need many more trained professionals. “Pharmaceutical and biotech industry might create 350,000 new jobs in the next ten years with regulatory reforms, according to Steven Ubl, the head of Pharmaceutical Research and Manufacturing Association, or PhRMA, but we don’t have anywhere near that number of people trained in the pharmaceutical sciences,” Khan said. “We have to be self-sufficient and shouldn’t depend on drugs manufactured elsewhere, and there is a tremendous opportunity here for education and training.” To that end, approval for master’s and doctorate programs in the College of Pharmacy is in the works, and Khan hopes students can begin taking classes in the fall of 2018. Collaboration is also key. “We need to bring our Health Science Center, engineering, veterinary medicine, AgriLife, life sciences and other programs together and have incentives for a multidisciplinary approach,” he said. “If people work together, there is no doubt they can bring down the cost with more efficient manufacturing processes, novel products and a more streamlined regulatory process.” “We cannot go on like this forever—some of these medications are just so expensive,” Khan added, “but if we avoid the greed displayed by some that have been identified in the media recently, and work together as a nation, there is no reason we cannot dramatically cut down on the price.”
Newswise — MINNEAPOLIS – Hospitals vary widely in how often they transition people with strokes from active treatment to comfort or hospice care within 48 hours after they get to the hospital, according to a new study published in the May 24, 2017, online issue of Neurology® Clinical Practice, an official journal of the American Academy of Neurology. “End-of-life and palliative care plays an important role with stroke, since the death rate is high, yet there has been limited data on the transition from treatment to comfort care,” said study author Shyam Prabhakaran, MD, MS, of Northwestern University Feinberg School of Medicine in Chicago. For the study, researchers looked at data on 963,525 people hospitalized for stroke in 1,675 hospitals over a four-year period. Of those people, 54,794 were given an order for early comfort measures only. Researchers found overall 5.6 percent of people were transitioned to early comfort measures only, but the percentage varied widely by hospital, from just 0.6 percent of those with stroke in some hospitals up to 37.6 percent in others. Transitioning people to early comfort measures only did decline over the four-year period of 2009 to 2013, from 6.1 percent to 5.4 percent. Researchers also found that people who were transitioned earliest to comfort care were more likely to have had an intracerebral or subarachnoid hemorrhage than an ischemic stroke. Intracerebral hemorrhage, a bleeding stroke, is when a blood vessel bursts inside the brain. Subarachnoid hemorrhage is when it bursts in the area between the brain and the tissues that cover it. Ischemic stroke is when there is a blockage of blood flow to the brain. People with the bleeding types of stroke are more likely to die or have disability than people with ischemic strokes. Further analysis found the following factors were independently associated with orders for early comfort measures only: older age, female sex, white race, Medicaid and self-pay or no insurance, arrival by ambulance, arrival during off-hours and being unable to walk. For stroke type, 19 percent of people with intracerebral hemorrhage received early comfort measures only, compared to 13 percent of those with subarachnoid hemorrhage and 3 percent of those who had an ischemic stroke. “The use of early comfort care varies widely between hospitals and is influenced by stroke type as well as the characteristics of both the hospitals and the people who are hospitalized,” Prabhakaran said. “Future studies are needed to better define how such decisions are made.” Prabhakaran noted that comfort care is different than do not resuscitate orders, which do not limit the use of intensive stroke treatments. Limitations of the study include being unable to evaluate level of consciousness, to see brain scans of the extent of injury from stroke and other factors that could affect the patients’ prognosis. Robert G. Holloway, MD, MPH, of the University of Rochester Medical Center in New York and a Fellow of the American Academy of Neurology, said in an accompanying editorial, “Severe stroke is a common event often close to one’s death that unleashes a series of intense conversations among doctors, patients and families about what health states are acceptable or unacceptable and what makes life worth living. This study gives us insights into how these transitions are happening and will stimulate discussion about how we can improve this process to help ensure that care is high quality and consistent with the patient’s goals.” To learn more about stroke, visit www.aan.com/patients. The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with 32,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.
Newswise — PHILADELPHIA— A new strategy – an injectable antibody – for lowering blood lipids and thereby potentially preventing coronary artery disease and other conditions caused by the build-up of fats, cholesterol, and other substances on the artery walls, is supported by findings from two new studies from researchers in the Perelman School of Medicine at the University of Pennsylvania. The new approach targets a protein called ANGPTL3, a regulator of enzymes that clear triglycerides and other fat molecules from the blood. Research in recent years has hinted that inherited mutations in the ANGPTL3 gene that disable its function can decrease triglyceride, LDL cholesterol and HDL cholesterol levels. As reported in a paper published online today in the New England Journal of Medicine, researchers from Penn Medicine, Regeneron Pharmaceuticals, and a group of international collaborators studied ANGPTL3 in both humans and mice. They found that blocking ANGPTL3 activity with an investigative injectable antibody, known as evinacumab, reduced triglycerides by up to 76 percent and lowered LDL cholesterol 23 percent in human study participants, and largely reversed signs of atherosclerosis in a mouse models. Researchers also included a human genetics study of approximately 188,000 people, which found that carriers of mutations that disable ANGPTL3 had nearly 40 percent fewer incidents of coronary artery disease as compared to those with fully functioning ANGPTL3. “In the clinic, I treat many patients with very high triglycerides, but our current medications aren’t lowering triglycerides enough in many cases. I’m delighted at the prospect of a new treatment that’s a lot more potent, all the more because it lowers LDL at the same time,” said study co-author Richard L. Dunbar, MD, assistant professor of Cardiovascular Medicine and member of Penn’s Division of Translational Medicine and Human Genetics. “It’s very reassuring to see that people with this genetic defect actually seem to be protected from heart disease. I think that really bodes well for a therapeutic that’s targeting the ANGPTL3 pathway.” In a separate study, published in the March issue of the Journal of the American College of Cardiology (JACC) researchers from Penn Medicine, Harvard Medical School, Washington University in St. Louis, and nine other institutions, who also studied humans and mice, reported on a similar set of findings. Among these was the discovery from another large population sample that carriers of ANGPTL3-inactivating mutations had a 34 percent lower rate of coronary artery disease compared to non-carriers. “We used different lines of evidence to show that ANGPTL3 deficiency is associated with a reduced risk of coronary artery disease,” said study co-author Kiran Musunuru, MD, PhD, MPH, an associate professor of Cardiovascular Medicine at Penn. “But ultimately we were able to identify that fact that carriers of this genetic mutation did in fact experience a benefit – with little other health risk.” A beneficial gene defect The trial of research on ANGPTL3 as a potential target for atherosclerosis prevention began over a decade ago when scientists reported on two cases of familial hypolipidemia, a rare inherited condition involving abnormally low blood levels of cholesterol and triglycerides. Most cases of familial hypolipidemia are linked to other gene mutations that cause liver and digestive problems, but in members of this American family with the condition, Musunuru found mutations in the gene for ANGPTL3, and no associated health problems. In the NEJM study from Dunbar and colleagues, the antibody had similar effects in an initial clinical trial in 83 people, lowering the blood levels of triglycerides measured after fasting by about 75 percent at the highest dose, and lowering LDL cholesterol by about 30 percent. Statins and other drugs are already widely used to lower LDL cholesterol, but there are fewer options for lowering triglycerides. “For treating high triglyceride levels there’s really nothing out there that’s quite this potent, so that’s where I expect this new approach to have its greatest therapeutic benefit,” Dunbar said. Hypertriglyceridemia, a condition in which fasting triglyceride levels are greater than 150 mg/dL, is estimated to affect at least tens of millions of American adults. It is associated with coronary artery disease and other forms of atherosclerosis, and can lead to potentially fatal inflammation of the pancreas. In principle, the strategy of targeting ANGPTL3 could have an even broader use in treating atherosclerosis in the general population. The researchers found that in a mouse model of atherosclerosis, treatment with evinacumab reduced the area of atherosclerotic lesions by 39 percent. The population study findings, including those from the JACC study, suggest that even the partial inactivation of ANGPTL3—carriers typically have one mutant copy of the gene and one working copy—may be powerfully protective against coronary artery disease, which has long been one of the leading causes of death in developed countries. In the JACC study, for example, carriers of inactivating ANGPTL3 mutations had only a 17 percent reduction in triglycerides on average. But that modest reduction was associated with a 34 percent reduction in coronary artery disease risk. Moreover, Musunuru and his colleagues found that the people in their sample with the lowest blood levels of ANGPTL3 had a 35 percent lower rate of heart attacks compared to those with the highest ANGPTL3 levels. Dunbar noted that the population study findings probably have lain to rest a lingering concern about targeting ANGPTL3, namely its effect in lowering not just LDL and triglycerides but also the so-called “good cholesterol,” known as HDL cholesterol. “If lowering HDL were a major concern, then I don’t think we would have seen the evidence of overall benefit that we did in this study,” he said. The two studies together suggest that single copies of inactivating ANGPTL3 mutations are found in roughly one of every 250 people of European descent, whereas people with mutations in both copies of the gene—as in the family studied by Musunuru and colleagues—are much rarer. According to Dunbar, the next logical step would be to take evinacumab into larger clinical trials to study its safety, effectiveness, and optimal dosing. “The effect of even a single dose lasts for several months, and it’s plausible that with multiple doses we would see an even deeper and more sustained effect,” he said. Additional Penn authors on the NEJM study include Scott Damrauer, MD, Aeron Small, and Daniel J. Rader MD, and the Journal of the American College of Cardiology study include Xiao Wang, PhD, Daniel J. Rader, MD, and Danish Saleheen, MBBS, PhD. Funding sources for the studies detailed in this press release included grants from the National Heart, Lung, and Blood Institute (NHLBI) (R01HL131961), (K08HL114642), (R01HL118744), (R01HL127564) and (R21HL120781) and Regeneron Pharmaceuticals. Editor’s Note: Dunbar has received grant support from and consulted for Regeneron Pharmaceuticals, Inc. ###
Newswise — Global leaders in cancer research have called for the worldwide sharing of cancer data to save lives. The Global Alliance for Genomics and Health argue how the ‘freeing of data’ for a disease that knows no borders will enable researchers to find better treatments that increase survival and improve quality of life for cancer patients Professor Mark Lawler at the Centre for Cancer Research and Cell Biology (CCRCB) at Queen’s University Belfast and lead author of the study said: “Current restrictions on data sharing across borders limit the data that can be used by researchers to carry out a comprehensive analysis of cancer. “This is particularly pertinent when researching rare types of cancer. If data is limited to a particular region or country, low patient numbers can make clinical research impossible. But it can also pose challenges with common cancers such as breast cancer, which is made up of different subtypes. We need as much information as possible to help develop new diagnostic tests and treatments for these different subtypes.” Charles Sawyers of the Memorial Sloan-Kettering Cancer Center in New York and co-author of the paper said: “If we get this right, we can really use the data to help us in our aspiration to improve outcomes in this deadly disease.” Taking the lives of over 8.5 million people every year, cancer is a global challenge demanding a global response. The paper, published in the New England Journal of Medicine (NEJM) was conducted by a coalition of world leading cancer experts under The Global Alliance for Genomics and Health and led by Queen’s University Belfast. World-leading cancer researchers highlight the urgent need to foster a more collaborative culture, to work together and share data for the benefit of cancer patients around the world. Professor Lawler said: “Such an aspiration depends on both effective collaboration as well as dedicated resources. We hope that our call for a ‘global cancer knowledge network’ energises the community to act decisively and provide the resources to embed data sharing for the benefit of cancer patients globally. If we do, then big data really can save lives.” “Our experience shows that patients want to get involved to make a positive difference so we need to help them to do that.” Recently, a group of patients with a rare gene mutation called ROS 1 that can cause different cancers came together online, frustrated about the lack of progress in the treatment of their disease. The online group involving over 130 individuals from eleven different countries approached a disease foundation and they are now involved in the first steps of developing a clinical trial that targets the particular genomic abnormality that causes their disease. Professor Lawler added: “We are working with the disease foundation to help make this clinical trial a reality. This exemplifies why accessing data is so vital to enable researchers to carry out their work and ultimately to help patients.” Margaret Grayson, a breast cancer survivor and Chair of the patient group, the Northern Ireland Cancer Research Consumer Forum explained: “Research is vital to improve the quality of life as well as life expectancy for cancer patients. Many patients will be more than willing to get involved and share their clinical information to bring us one step closer to tackling this global health issue.” The paper, ‘Sharing Clinical and Genomic Data on Cancer – The Need for Global Solutions’ is being published in the New England Journal of Medicine (NEJM) on 25 May.