Newswise — In a research effort that merged genetics, physics and information theory, a team at the schools of medicine and engineering at The Johns Hopkins University has added significantly to evidence that large regions of the human genome have built-in variability in reversible epigenetic modifications made to their DNA. In a report on the research published March 27 in Nature Genetics, the team says the findings also suggest that such epigenetic variability is a major factor in the ability of cancer cells to proliferate, adapt and metastasize. "These results suggest that biology is not as deterministic as many scientists think," says Andrew Feinberg, M.D., M.P.H., the King Fahd Professor of Medicine, Oncology, and Molecular Biology and Genetics at the Johns Hopkins University School of Medicine and director of the Center for Epigenetics in the Institute for Basic Biomedical Sciences. "If so, they could have major implications for how we treat cancer and other aging-related diseases." Epigenetic modifications, achieved along the genome by the chemical attachment of methyl molecules, or tags, to DNA, are reversible changes that alter which genes are turned on or off in a given cell without actually altering the DNA sequence of the cell. Such changes enable a complex organism, like a human, to have a wide range of different tissues that all still have the exact same genetic template. However, in some studies with laboratory mice, Feinberg had observed that these epigenetic tags varied considerably among the mice even when comparing the same type of tissue in animals that have been living in the exact same conditions. "These weren't minor differences, and some very important genes were involved," Feinberg says. Feinberg, who is also a Bloomberg Distinguished Professor of Engineering and Public Health at The Johns Hopkins University, suspected that this variation might be an adaptive feature by which built-in epigenetic randomness would give some cells an advantage in rapidly changing environments. To find out if that was the case, he teamed up with John Goutsias, Ph.D., professor of electrical and computer engineering at the Johns Hopkins Whiting School of Engineering, to find a way to measure this controlled type of randomness, scientifically termed epigenetic stochasticity, by using the information-theoretic concept of Shannon entropy. Using a mathematical model known as the Ising model, invented to describe phase transitions in statistical physics, such as how a substance changes from liquid to gas, the Johns Hopkins researchers calculated the probability distribution of methylation along the genome in several different human cell types, including normal and cancerous colon, lung and liver cells, as well as brain, skin, blood and embryonic stem cells. As Goutsias explains, this distribution reflects the chance that a particular region of a genome will be methylated in a population of similar cells. In areas of low randomness, this probability would mostly be 0 or 100 percent, but in areas of high randomness, the numbers would be 50-50 or thereabouts. The analysis revealed that the human genome is organized into large pieces of low or high epigenetic stochasticity, and that these regions correspond to areas of chromosomes that are structurally different in the cell nucleus. Feinberg thinks that a main function of a cell's nucleus might be to partition the genome to make sure that regions of low or high stochasticity are well-defined. The other significant finding of the study, says Garrett Jenkinson, Ph.D., assistant research scientist at the Johns Hopkins Whiting School of Engineering who carried out much of the analyses, was that this variability goes haywire in cancer cells, which may display significant regional differences in methylation stochasticity compared to normal cells. Based on the evolutionary idea that targeted epigenetic stochasticity can improve adaptation, these observations could explain how cancer cells are good at evading chemotherapy treatments and spreading from one part of the body to another, he adds. "Researchers have understood the importance of epigenetics in driving cancer growth, but the focus has been trying to reverse epigenetic changes to specific genes," Feinberg says. "We need to readjust and think more broadly about the epigenetic process as a whole." Looking at ways to reverse aberrant changes in variability to make cancer cells more epigenetically controlled should be a target for therapy, he adds. Earlier this year, Feinberg led a study that considered this view of epigenetics in metastatic pancreatic cancer cells. Using an experimental drug called 6-aminonicotinamide, his group reversed the large-scale epigenetic changes that enabled the tumor cells in mice to metastasize and slow the growth of further tumors. In addition to Goutsias, Feinberg, and Jenkinson, Elisabet Pujadas, a graduate student in the Center for Epigenetics at Johns Hopkins University School of Medicine contributed to this study. This study was supported by grants from the National Institutes of Health (R01CA054358, DP1ES022579, and AG021334) and National Science Foundation (CCF-1217213 and CCF-1656201).
Newswise — BETHESDA, MD, – Cancer prevention advocates and researchers have designated March 22nd as National Lynch Syndrome Awareness Day. Carol A. Burke, MD, FACG, President of the American College of Gastroenterology (ACG), a gastroenterologist specializing in hereditary colorectal cancer syndromes at the Cleveland Clinic in Cleveland, OH, offered commentary and guidance for GI physicians on Lynch Syndrome in an ACG communication to her colleagues. According to Dr. Burke, up to approximately 1 million Americans are estimated to live with Lynch Syndrome, and it is believed that as many as 500,000 Lynch Syndrome carriers have no idea they are at risk of disease. Lynch Syndrome is the most common inherited colorectal cancer syndrome. It accounts for three to five percent of all cases of colorectal cancer and 10 to 15 percent of colorectal cancers diagnosed in patients younger than age 50. Lynch Syndrome is also the most common inherited cause of endometrial cancer. It causes up to three percent of all endometrial cancers. Individuals with Lynch Syndrome have a substantially increased lifetime cumulative risk of colorectal cancer and other Lynch Syndrome-associated cancers including endometrial, ovarian, gastric, small bowel and urothelial tract. “Physicians should be reminded on this day to redouble our efforts to create opportunities in our practice to make a proactive diagnosis of Lynch Syndrome by utilizing simple and directed family cancer history taking, ensuring that all colorectal cancers in our patients are tested for evidence of microsatellite instability, a hallmark of Lynch Syndrome, seeing that appropriate patients and families are offered genetic testing, and providing them with the education and management schema to prevent death from Lynch Syndrome-related cancers,” Dr. Burke advised. “Prevention of the occurrence and death from some of these cancers due to Lynch Syndrome is possible with recognition of the syndrome and preventive strategies, such as colonoscopy and prophylactic surgery,” she added. About Lynch SyndromeLynch Syndrome, named after Dr. Henry T. Lynch who characterized the syndrome in 1966, is an autosomal dominant hereditary cancer syndrome. It is caused by a germline mutation in one of the DNA mismatch repair (MMR) or EPCAM genes. Impact of Lynch Syndrome on FamiliesLynch Syndrome affects families. Once it is diagnosed by genetic testing in one relative, other at-risk family members should undergo genetic testing and be offered appropriate management to decrease their risk of cancer. Importance of Molecular and Genetic TestingData show that the family history alone is not accurate enough to select which patients should be tested for Lynch Syndrome. Some studies have shown that up to 40 percent of patients with Lynch Syndrome do not meet clinical criteria for the syndrome. In her commentary, Dr. Burke emphasizes that molecular and genetic testing is required to make the diagnosis of Lynch Syndrome. Currently, the national recommendation is that all colorectal cancer tumors should be tested for evidence of MMR deficiency to reveal Lynch Syndrome. This is called “universal testing” and is endorsed by many organizations and agencies. Many commercial laboratories offer genetic testing for Lynch Syndrome. Genetic counselors are invaluable in the process of risk assessment and providing genetic testing. The National Society of Genetic Counselors can provide information for a genetic counselor in your area (www.nsgc.org). Dr. Burke offers a warning to her fellow gastroenterologists, “Be sure your Lynch Syndrome patients know that this is a ‘family business’ and provide them with recommendations to share with their family members, a lifesaving gesture!” Read Dr. Burke’s guidance for GI clinicians on Lynch Syndrome via the ACG Blog (acgblog.org/2017/03/20/acg-presidents-blog-lynch-syndrome-awareness-day). Access patient education on Lynch Syndrome from the ACG patient website (patients.gi.org/topics/lynch-syndrome). Access resources from Lynch Syndrome International on its website (lynchcancers.com) and Facebook page (facebook.com/LynchSyndromeInternational). About the American College of Gastroenterology: Founded in 1932, the American College of Gastroenterology (ACG) is an organization with an international membership of more than 14,000 individuals from 85 countries. The College's vision is to be the pre-eminent professional organization that champions the evolving needs of clinicians in the delivery of high-quality, evidence-based and compassionate health care to gastroenterology patients. The mission of the College is to advance world-class care for patients with gastrointestinal disorders through excellence, innovation and advocacy in the areas of scientific investigation, education, prevention and treatment. www.gi.org. For more information on colorectal cancer screening, gi.org/ColonCancer. Follow ACG on Twitter @AmCollegeGastro.
Newswise — By the time someone realizes they damaged a ligament, tendon or cartilage from too much exercise or other types of physical activity, it’s too late. The tissue is stretched and torn and the person is writhing in pain. But a team of researchers led by University of Utah bioengineering professors Jeffrey Weiss and Michael Yu has discovered that damage to collagen, the main building block of all human tissue, can occur much earlier at a molecular level from too much physical stress, alerting doctors and scientists that a patient is on the path to major tissue damage and pain. This could be especially helpful for some who want to know earlier if they are developing diseases such as arthritis or for athletes who want to know if repeated stress on their bodies is taking a toll. “The scientific value of this is high because collagen is everywhere,” Yu says. “When we are talking about this mechanical damage, we’re talking about cartilage and tendons and even heart valves that move all the time. There are so many tissues which involve collagen that can go bad mechanically. This issue is important for understanding many injuries and diseases.” The team’s research, funded by the National Institutes of Health, was published this week in the latest issue of Nature Communications. Before, scientists thought collagen — which are strands of protein braided into a ropelike structure that give tissue its strength and stiffness — would just stretch or slide by each other during repeated stress. They never knew if they actually got damaged. As a result, patients who put repeated stress on their body would not know if they were on the road to something worse from tough physical activity. But now the team discovered that the collagen molecule does in fact get unraveled at a molecular level before complete failure of the tissue occurs. This type of minor damage, called “subfailure damage,” is associated with common injuries to connective tissues such as ligament and meniscus tears and various types of tendinitis such as tennis elbow and rotator cuff tendinopathy. “Accumulation of subfailure damage can go on for a long time with no catastrophic failure, but repeated damage results in inflammation,” says Weiss, “So this vicious cycle continues, the inflammation breaks down the tissue, making it more susceptible to damage, which then can result in a massive tear.” The team used a new probe called collagen hybridizing peptide (CHP), a tiny version of collagen that binds to unraveled strands of damaged collagen, to figure out where and how much damage has occurred in overloaded tendons. This paves the way for medical researchers to use CHP probes in the future as a way of diagnosing if a person has damaged collagen and if so, how much and where, before a massive tear happens. Weiss and Yu also believe it can be used as a way to deliver drugs straight to the damaged tissue because the CHP targets only the damaged collagen. Finally, it will tell doctors even more about what happens to our bodies during repeated physical activity. “A fundamental understanding of the loads and strain that cause molecular damage has eluded us until now,” says Weiss. “Our findings can translate into recommendations for athletes on how to train or what rehabilitation protocols people who are injured can use.” Co-authors include researchers in the Department of Bioengineering at the University of Utah (Jared Zitnay, Yang Li, Boi Hoa San and Shawn Reese) and the Department of Civil and Environmental Engineering at Massachusetts Institute of Technology (Markus Buehler, Zhao Qin and Baptiste DePalle. The CHP probe has been commercialized by 3Helix, Inc, based in Salt Lake City, Utah. This news release and photos may be downloaded from: http://unews.utah.edu
Newswise — Researchers at Bascom Palmer Eye Institute, part of the University of Miami Miller School of Medicine, have identified a new molecule that induces the formation of abnormal blood vessels in the eyes of diabetic mice. The study, “Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy,” which will be published March 22 in The Journal of Experimental Medicine, suggests that inhibiting this molecule may prevent similarly aberrant blood vessels from damaging the vision of not only diabetics, but also premature infants. Changes in the vasculature of diabetes patients can cause long-term complications such as diabetic retinopathy, which affects around 93 million people worldwide. Many of these patients suffer a dramatic loss of vision as the blood vessels supplying the retina become leaky and new, abnormal blood vessels are formed to replace them. A molecule called vascular endothelial growth factor (VEGF) regulates blood vessel growth and leakiness, and two VEGF inhibitors, ranibizumab (Lucentis) and aflibercept (Eylea), have been approved to treat retinal vascular leakage, though they are only successful in about a third of patients. The growth of abnormal new blood vessels also causes retinopathy of prematurity (ROP), the most common cause of vision loss in children that affects up to 16,000 premature infants per year in the US. VEGF inhibitors are not approved for use in these patients because VEGF is crucial for vascular development in newborn children. Study lead-author Wei Li, Ph.D., research associate professor, and his colleagues at Bascom Palmer developed a technique called “comparative ligandomics” to identify additional molecules that regulate the behavior of blood vessels in diabetic mice. The approach allows the researchers to compare the signaling molecules that selectively bind to the surface of retinal blood vessel cells in diabetic but not healthy animals.“It is estimated that between one third and one half of all marketed drugs act by binding to cell surface signaling molecules or their receptors,” says Li. “Our ligandomics approach can be applied to any type of cell or disease to efficiently identify signaling molecules with pathogenic roles and therapeutic potential.” Using this technique, Li and colleagues discovered that a protein called secretogranin III (Scg3) efficiently binds to the surface of retinal blood vessel cells in diabetic, but not healthy, mice. Though Scg3 promotes the secretion of hormones and other signaling factors, it wasn’t thought to have a signaling function itself. Nevertheless, the researchers found that Scg3 increased vascular leakage, and, when administered to mice, it stimulated blood vessel growth in diabetic, but not healthy, animals. VEGF, in contrast, stimulates blood vessel growth in both diabetic and healthy mice. Li and colleagues think that Scg3 binds to a distinct cell surface receptor that is specifically up-regulated in diabetes. Treating diabetic mice with Scg3-neutralizing antibodies dramatically reduced the leakiness of their retinal blood vessels. Moreover, the antibodies significantly inhibited the growth of new blood vessels in mice with oxygen-induced retinopathy, a well-established animal model of human ROP. Though the researchers still need to confirm the role of Scg3 in humans, inhibiting this protein could be an effective treatment for both diabetic retinopathy and ROP, especially as it appears to have no role in normal vascular development. “Scg3 inhibitors may offer advantages such as disease selectivity, high efficacy, and minimal side effects,” Li says. “Because they target a distinct signaling pathway, anti-Scg3 therapies could be used in combination with, or as an alternative to, VEGF inhibitors.” LeBlanc et al. 2017. J. Exp. Med. http://jem.rupress.org/cgi/doi/10.1084/jem.20161802?PR # # #
Newswise — ANN ARBOR, Mich. — Parents often want medical advice when their child gets sick but only about half are very confident they can get a same day appointment with their child’s provider, a new national poll finds. Forty-two percent of parents say they would take their child to an urgent care, retail clinic or emergency department if their child woke up with a sore throat and fever, according to the C.S. Mott Children’s Hospital National Poll on Children’s Health. But the poll also found that many parents would try to communicate with their child’s provider without an office visit, with 42 percent saying they would call for advice. More parents were confident they could get same-day phone advice (60 percent) than get in to see the doctor (53 percent). Just 10 percent of parents would use email to discuss a sick child’s health issues with their child’s provider. “Most parents want timely medical advice when their child is sick, and it can be frustrating when they don’t feel like they have immediate access to a health care provider,” says Mott poll co-director and pediatrician Gary Freed, M.D. “More parents seem to be utilizing alternatives to a traditional office visit, such as having a consult by phone. Our poll found that four in 10 parents would turn to a walk-in option like urgent care if their child woke up in the morning with a sore throat and fever. While these services may seem convenient, parents should recognize that these providers may not be familiar with their child’s medical history and insurance coverage may be limited.” Freed notes that many offices have a limited number of “sick visits” available each day and these may fill up quickly, especially in winter months or during an outbreak of an illness like the flu. However, phone or email advice may also be an option for minor illnesses and parents are encouraged to consider those routes before seeking emergency care. “When parents are picking a doctor for their child, they should discuss these types of situations ahead of time so they know what type of arrangements are made for urgent visits or advice,” Freed says. “Every provider has a different system in place to address parent concernswhen their child is ill, and parents should look for one that best matches their expectations. More often than not, a primary care office is still the most convenient, cost efficient place to get the care and health advice your child needs.” The poll is based on responses from a national sample of 2,036 parents of children 0-18 years of age who were asked about their experiences trying to get health care advice or a provider visit for a sick child. Read the full Mott poll report here: http://mottnpch.org/reports-surveys/sick-kids-can-parents-get-same-day-doctor-appointments
Newswise — Montreal – A study by researchers at the University of Montreal Hospital Research Centre (CRCHUM) shows that more than half of family doctors in Canada are still using manual devices to measure blood pressure, a dated technology that often leads to misdiagnosis. “About 20% of people receiving treatment for hypertension don’t actually have a problem and do not need medication. This is due mainly to the fact that their blood pressure was improperly measured,” said lead author Janusz Kaczorowski, whose study was recently published in the journal Canadian Family Physician. Kaczorowski, a medical sociologist, is a CRCHUM researcher and professor in the Department of Family and Emergency Medicine at Université de Montréal. Getting one’s blood pressure taken during a visit to the doctor is a routine procedure. It also provides crucial medical data. In Canada, one adult in five suffers from hypertension which represents the greatest global risk factor for death and disability. Blood pressure is defined as the pressure that the blood exerts on artery walls. Measured in the arm artery, it is expressed in two numbers: the value when the heart contracts (systolic blood pressure) and the value when the heart relaxes between two contractions (diastolic blood pressure). Blood pressure is considered normal when systolic pressure is below 140 mmHg and diastolic pressure is below 90 mmHg. Above these values, a person is said to have high blood pressure (hypertension). The technology behind tensiometers or sphygmomanometers, the devices used to measure blood pressure, has changed a great deal over the last 20 years. Today, automatic electronic measuring devices, known as oscillometric devices, are available. In 2016, The Canadian Hypertension Education Program (CHEP) Guidelines recommended that electronic measurement is preferable to manual measurement. An increasing number of medical clinics are equipped with automatic electronic devices. Yet in the spring of 2016, Kaczorowski’s team conducted a survey among Canadian family doctors: 52% of the 769 respondents indicated that they used a manual tensiometer to measure blood pressure. Only 43% used an automatic device. “Clinicians should use automatic devices," Kaczorowski said. "They are more expensive but more precise because they take several measurements. Manual measurement is acceptable if it’s properly done, but that’s often not the case. To take blood pressure the right way, a 12- to 15-minute period is required. We know that the average visit to a family doctor lasts 10 minutes. We have to rethink how patient visits are organized so that the patient can be left alone in a room while the measurement is taken." Automated measurement has the advantage of eliminating what’s known as white-coat syndrome, which refers to artificially high blood pressure resulting from the stress of being in a doctor’s office and human interaction. The researchers believe that clinicians should adopt these devices to detect individuals likely to suffer from high blood pressure, in accordance with the Canadian guidelines. In Canada, healthcare costs attributable to hypertension were evaluated at more than $13 billion in 2010. “If people who take high-blood-pressure medication had their blood pressure measured incorrectly, the financial implications are considerable, in addition to the side effects, which could be avoided,” said Kaczorowski. The CHEP Guidelines state that modifying health-related behaviours is an efficient way of preventing and treating high blood pressure and of reducing the risk of cardiovascular disease. It is possible to lower blood pressure through a healthy diet, regular physical activity, moderate alcohol consumption, reduced intake of dietary sodium, avoidance of exposure to tobacco products, and stress management. To find out more, please visit: www.hypertension.ca About this studyThe study How do family physicians measure blood pressure in routine clinical practice? A national survey of Canadian family physicians was published on March 14, 2017 in Canadian Family Physician. To find out more, the study is available at: www.cfp.ca/content/63/3/e193.full.pdf+html -30- SEE ORIGINAL STUDY
Newswise — Patients with benign breast tumors may be eligible for a new focused ultrasound–based investigational treatment as part of a pivotal, multi-center clinical study. The trial began last month at the University of Virginia (UVA) Medical Center. David Brenin, MD, Associate Professor of Surgery and Chief of Breast Surgery at UVA, is the Principal Investigator for the trial. He recently completed a 20-patient pilot study to test the safety and efficacy of the device, Theraclion’s EchoPulse system. Now, in this single arm prospective study, the procedure will be performed in 100 patients at several sites worldwide, including UVA, Montefiore Medical Center, Columbia Presbyterian, Bellevue Hospital Center in New York, and others. As these new sites begin treating, the list of locations will be updated on our website and on clinicaltrials.gov.“The patient selection criteria have been updated since the pilot study,” says Dr. Brenin. “The new parameters for the size of the fibroadenoma and the range of symptoms should allow us to include more patients. Furthermore, our experience and improvements to the device have allowed us to decrease the overall treatment time.” EchoPulse is designed to non-invasively ablate benign breast tumors using ultrasound-guided focused ultrasound treatment. Although it is not yet approved by the US Food and Drug Administration, the system received the CE Mark in Europe five years ago, where it is also used to treat breast fibroadenomas and treat thyroid nodules and is also under investigation for other conditions. “If this multi-center trial is successful, we will seek regulatory approval in the US,” says Theraclion’s Chief Medical Officer, Michel Nuta, MD. “Approval by the FDA would allow many more women to receive precise treatment of breast fibroadenomas non-invasively and on an outpatient basis, enabling them to return to their daily lives almost immediately.” Patients who are interested in this study at the University of Virginia (IRB# 19437) should contact Research Coordinator Katie Rea via phone (434) 243-0315 or email email@example.com. More information for patients and referring physicians can also be found on the UVA website. Dr. Brenin plans to present the initial data from the pilot study at the 18th Annual Meeting of the American Society of Breast Surgeons in Las Vegas in April 2017. READ THERACLION’S PRESS RELEASE > About Focused UltrasoundFocused ultrasound uses ultrasonic energy guided by real-time imaging to treat tissue deep in the body without incisions or radiation. Multiple intersecting beams of ultrasound are directed and concentrated on a target, much like a magnifying glass can focus multiple beams of light on a single point. Where each individual beam passes through the tissue, there is no effect. But, at the focal point, the convergence of the beams of focused ultrasound energy results in many important biological effects depending on the nature of the tissue and the ultrasound parameters. Today, focused ultrasound is approved in the United States to treat essential tremor, uterine fibroids, reduce pain from bone metastases and treat the prostate. Different systems are approved to treat 22 diseases in regions around the world. The technology is in various stages of research and development for more than 70 diseases, including Parkinson’s, Alzheimer’s, hypertension and tumors of the brain, liver, breast and pancreas. About the Focused Ultrasound FoundationThe Focused Ultrasound Foundation was created to improve the lives of millions of people worldwide by accelerating the development of focused ultrasound, an early-stage, noninvasive, therapeutic technology with the potential to transform the treatment of many serious medical disorders. The Foundation works to clear the path to global adoption by coordinating and funding research, fostering collaboration, and building awareness among patients and professionals. It is dedicated to ensuring that focused ultrasound finds its place as a mainstream therapy for a range of conditions within years, not decades. Since its establishment in 2006, the Foundation has become the largest non-governmental source of funding for focused ultrasound research. More information can be found at www.fusfoundation.org.
Newswise — Unlike its viral cousins hepatitis A and B, hepatitis C virus (HCV) has eluded the development of a vaccine and infected more than 170 million people worldwide. Now, researchers at Johns Hopkins Medicine report that a novel laboratory tool that lets them find virus mutations faster and more efficiently than ever before has identified a biological mechanism that appears to play a big role in helping HCV evade both the natural immune system and vaccines. For their study, described March 8 in PLOS Pathogens, the researchers used one of the largest libraries of naturally occurring HCV to rapidly sort out which mutations allow HCV to evade immune responses and found that mutations that occur outside of the viral sites typically targeted by such antibody responses play a major role in the virus' resistance. "We think those mutations could account for the difficulty of making an effective vaccine," says Justin Bailey, M.D., Ph.D., assistant professor of medicine at the Johns Hopkins University School of Medicine. All told, the researchers compiled a library of 113 HCV strains from 27 patients with HCV infections followed at The Johns Hopkins Hospital. The researchers then tested each strain of the virus for susceptibility to two potent and commonly used antibodies in vaccine development experiments for HCV, HC33.4 and AR4A. Because natural HCVs do not thrive in the lab, the researchers first created pseudo-viruses using the contents and capsule of HIV, a virus that grows easily in the lab. Then, by placing surface proteins of each HCV virus onto these pseudoviruses, the researchers were able to efficiently infect human cells with the HCV strains in tissue culture. One-third of the cells infected with each strain received treatment with HC33.4 antibodies, one-third received treatment with AR4A antibodies and a final third (the control group) received no treatment. The researchers then compared the level of infection in the treated cells against the untreated cells. The investigators observed that HC33.4 and AR4A neutralized only 88 percent and 85.8 percent of the virus, respectively. "We discovered that there was a lot of naturally occurring resistance, meaning we may need to greatly expand the set of viruses we use to evaluate potential vaccines," says Ramy El-Diwany, a student at the Johns Hopkins University School of Medicine and first author of the study. The team also found that the effectiveness of the antibodies varied, with some viral strains very inhibited by the antibodies and others hardly affected at all. To find out what was causing the variation, the researchers next tapped into the HCV genomes. Using a program that compared the genetic sequences of each viral strain, the researchers were able to analyze which mutations conferred resistance to each strain of the virus. They found that despite wide-ranging levels of resistance to HC33.4 and AR4A, the areas that allow these antibodies to bind to the virus barely varied. The HC33.4 binding site mutated at only one location, for example, and the AR4A binding site was the same across all viral strains. The researchers then expanded their search to the proteins on the surface of HCV. They found that while mutations in the binding site were not associated with resistance, other mutations in the surface proteins away from the binding site correlated with viruses that persisted despite antibody treatment. "These are the mutations we believe may allow the viruses to avoid being blocked by antibodies altogether. If you think of it like a race, the antibody is trying to bind to the virus before it can enter the cell. We think this mutation may allow the virus to get into the cell before it even encounters the immune system," says Bailey. HCV is spread from person to person through contact with the blood of an infected person. Some patients are able to fight off the infection naturally, but for 70 to 85 percent of people, the infection becomes chronic. A new HCV infection is effectively treated with direct-acting antiviral drugs, but the researchers say a preventive vaccine is needed to control what they call an HCV pandemic because as many as 50 percent of people infected are unaware that they carry the virus, putting others at risk of infection. Treatment does not protect those at risk from future infection by HCV. "HCV is very unlikely to be eliminated by treatment alone," says El-Diwany. Other researchers involved in this study include Valerie Cohen, Madeleine Mankowski, Lisa Wasilewski, Jilian Brady, Anna Snider, William Osburn and Stuart Ray of the Johns Hopkins University School of Medicine, and Ben Murrell of the University of California, San Diego. This research was funded by the National Institute of Allergy and Infectious Diseases Extramural Activities (1K08 AI102761, U19 AI088791), the National Institute of Drug Abuse (R37 DA013806), and the Johns Hopkins University Center for AIDS Research (1P30AI094189).
Newswise — Results of a new study by Johns Hopkins researchers using national data add to evidence that living in inner cities can worsen asthma in poor children. They also document persistent racial/ethnic disparities in asthma. A report of the study's findings, published in The Journal of Allergy and Clinical Immunology on March 8, shows that urban living and black race are strong independent risk factors for increased asthma morbidity -- defined as higher rates of asthma-related emergency room visits and hospitalizations -- but urban living does not increase the risk for having asthma. "Our findings serve as evidence that there are differences between risk factors linked to developing asthma and those linked to making asthma worse if you already have it," says Corinne Keet, M.D., Ph.D., associate professor of pediatrics at the Johns Hopkins University School of Medicine and the paper's lead author. To the researchers' knowledge, few previous studies have been conducted on a national level to determine the effects of inner-city living on both asthma prevalence and severity. While Keet's previous work published in 2015 using a national survey showed that living in an urban area was not a risk factor for having asthma, that study didn't allow for analysis of asthma morbidity. The research team sought to determine those effects by analyzing information gathered by the U.S. Centers for Medicare and Medicaid Services on the health care utilization of 16,860,716 children ages 5 to 19 who were enrolled in Medicaid in 2009 and 2010. The team first narrowed the pool of data to children who had at least one asthma-related outpatient or Emergency Department visit over the two-year period. Based on the county they lived in, these 1,534,820 children were categorized by urbanization status and based on their ZIP code, categorized as living in a poor or not poor neighborhood. Urbanization status identification took into account locations including urban, suburban, medium metro, and a category that combined smaller metro and rural regions. Inner-city residence was defined as living in an urban county and ZIP code where at least 20 percent of households were below the federal poverty line, defined as an income of less than $22,050 for a family of four in 2009. The team excluded states that were missing more than 10 percent of data on race/ethnicity, states in which all major race/ethnicity groups were not represented and states that did not have urban areas. The results for 18 states that met the study's final guidelines showed that children who lived in nonurban areas were 18 to 21 percent less likely to be at risk for hospitalizations, even after accounting for race/ethnicity. The researchers also found that compared to non-Hispanic white children, black children and children of "other" races had 89 and 61 percent, respectively, higher risks of asthma-related hospitalizations. Unlike other racial/ethnic groups, Hispanic children who live in a nonurban area did not experience reduced risks of emergency room visits or hospitalizations. And contrary to Keet's previous studies, which reported that poverty was protective against asthma prevalence rates for Hispanic children, the team found no similar association for asthma morbidity. Keet says that among the Medicaid population she studied, 30 percent of asthma-related hospitalizations were likely attributable to socioeconomic, geographic and/or racial/ethnic disparities; 19 percent of hospitalizations were estimated to be attributable to black race/ethnicity; 4 percent were attributable to living in a poor area; and 7 percent were attributable to living in an urban area. Children who lived in inner-city areas had an overall 40 percent higher risk of asthma-related emergency room visits and 62 percent higher risk of asthma-related hospitalizations. After adjusting for race/ethnicity, risk was lowered to 14 percent and 30 percent higher for emergency room visits and hospitalizations, respectively. While this study did not look at any specific environmental exposures associated with urbanization, the findings are in keeping with previous work that shows that certain risk factors concentrated in urban areas, such as exposure to mice and cockroach allergens and air pollution, are associated with asthma morbidity. Keet says the new study affirms her team's earlier finding that asthma rates or prevalence were not affected by residing in inner-city areas, strengthening evidence that risk factors for the cause of asthma are independent of those that worsen it. For example, exposure to pest allergens is associated with increased asthma morbidity but protects high-risk children from developing allergies. "These results show that despite several decades of research on racial/ethnic and geographic disparities in asthma morbidity, there are still very large differences in rates of emergency room visits and hospitalizations by race and neighborhood characteristics. These findings emphasize that we need to redouble our efforts to find comprehensive solutions to address asthma disparities," concludes Keet. The study's two main limitations were that not all states could be included because of differences in Medicaid data collection, and that it is possible that some of the differences in emergency room visits and hospitalizations could be related to how patients seek care for asthma, rather than only reflecting underlying disease severity.
BUFFALO, N.Y. — A discovery, several years in the making, by a University at Buffalo research team has proven that adult skin cells can be converted into neural crest cells (a type of stem cell) without any genetic modification, and that these stem cells can yield other cells that are present in the spinal cord and the brain. The applications could be very significant, from studying genetic diseases in a dish to generating possible regenerative cures from the patient’s own cells. “It’s actually quite remarkable that it happens,” says Stelios T. Andreadis, PhD, professor and chair of UB’s Department of Chemical and Biological Engineering, who recently published a paper on the results in the journal Stem Cells. The identity of the cells was further confirmed by lineage tracing experiments, where the reprogrammed cells were implanted in chicken embryos and acted just as neural crest cells do. Stem cells have been derived from adult cells before, but not without adding genes to alter the cells. The new process yields neural crest cells without addition of foreign genetic material. The reprogrammed neural crest cells can become smooth muscle cells, melanocytes, Schwann cells or neurons. “In medical applications this has tremendous potential because you can always get a skin biopsy,” Andreadis says. “We can grow the cells to large numbers and reprogram them, without genetic modification. So, autologous cells derived from the patient can be used to treat devastating neurogenic diseases that are currently hampered by the lack of easily accessible cell sources.” The process can also be used to model disease. Skin cells from a person with a genetic disease of the nervous system can be reprogrammed into neural crest cells. These cells will have the disease-causing mutation in their chromosomes, but the genes that cause the mutation are not expressed in the skin. The genes are likely to be expressed when cells differentiate into neural crest lineages, such as neurons or Schwann cells, thereby enabling researchers to study the disease in a dish. This is similar to induced pluripotent stem cells, but without genetic modification or reprograming to the pluripotent state. The discovery was a gradual process, Andreadis says, as successive experiments kept leading to something new. “It was one step at a time. It was a very challenging task that took almost five years and involved a wide range of expertise and collaborators to bring it to fruition,” Andreadis says. Collaborators include Gabriella Popescu, PhD, professor in the Department of Biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB; Song Liu, PhD, vice chair of biostatistics and bioinformatics at Roswell Park Cancer Institute and a research associate professor in biostatistics UB’s School of Public Health and Health Professions; and Marianne Bronner, PhD, professor of biology and biological engineering, California Institute of Technology. Andreadis credits the persistence of his then-PhD student, Vivek K. Bajpai, for sticking with it. “He is an excellent and persistent student,” Andreadis says. “Most students would have given up.” Andreadis also credits a seed grant from UB’s office of the Vice President for Research and Economic Development’s IMPACT program that enabled part of the work.The work recently received a $1.7 million National Institutes of Health grant to delve into the mechanisms that occur as the cells reprogram, and to employ the cells for treating the Parkinson’s-like symptoms in a mouse model of hypomyelinating disease.“This work has the potential to provide a novel source of abundant, easily accessible and autologous cells for treatment of devastating neurodegenerative diseases. We are excited about this discovery and its potential impact and are grateful to NIH for the opportunity to pursue it further,” Andreadis said. The research, described in the journal Stem Cells under the title “Reprogramming Postnatal Human Epidermal Keratinocytes Toward Functional Neural Crest Fates,” was supported by grants from the National Institutes of Health. SEE ORIGINAL STUDY