UCI-led study reveals how blood cells help wounds heal scar-free Insights into the diversity of wound fibroblasts Irvine, Calif., Feb. 08, 2019 — New insights on circumventing a key obstacle on the road to anti-scarring treatment have been published by Maksim Plikus, an associate professor in developmental and cell biology at the UCI School of Biological Sciences and colleagues in Nature Communications. The research team discovered that the natural scar-free skin repair process relies partially on assistance from circulating blood cells. The results point the way toward possible treatments for scar-free wound healing that target the body’s own blood cells. Skin injuries activate rapid wound repair, which often culminates with the formation of scars. Unlike normal skin, scars are devoid of hair follicles and fat cells, and creating new hair and fat is necessary for regenerating an equivalent of normal skin. In a 2017 paper published in Science, Plikus and colleagues identified that adult mice can naturally regenerate nearly normal-looking skin when new hair follicles and fat cells form in healing wounds. New fat cells regenerate from myofibroblasts, a type of wound fibroblast that was previously not thought to be capable of converting into other cell types. This discovery brought renewed attention to wound fibroblasts as attractive targets for anti-scarring therapies. In the current study, co-led by George Cotsarelis from University of Pennsylvania, the research team sought to further characterize wound fibroblasts and determine if they’re all the same and equally capable of regenerating new fat cells. Using a panel of single-cell tools as a type of “computational microscope” that examines thousands of individual cells at once, the research team observed an unexpectedly high degree of fibroblast diversity. “We saw that wound fibroblasts are surprisingly very diverse and that there are as many as twelve different cell sub-types. We understand their molecular signatures and are beginning to learn about their unique biology. For example, we already know that distinct fibroblast sub-types ‘prefer’ only certain parts of the wound. This suggests that they play specific roles in different locations within the wound, and possibly at different times during the repair process,” said Christian Guerrero-Juarez, a postdoctoral fellow at UCI and first author on the project. After a closer look at wound fibroblasts, the team noted that a sizable group of cells had the molecular telltale signs of having originated from blood. “Molecular profiling of wound fibroblasts strongly suggests that as many as 13% of them at some point in their past were blood cells that converted into collagen-producing fibroblasts, but kept residual blood-specific genes still turned on,” said Plikus. Indeed, blood cell-derived fibroblasts have been reported by others in the past, including located in wound scars. “What is truly novel about our observation is that these fibroblast-making blood cells, which are called myeloid cells, can reprogram into new fat cells,” Plikus said. “In essence, we observed that for wounds to achieve scar-less regeneration, the body must mobilize multiple cellular resources, which includes remotely circulating blood progenitors.” Because myeloid cells can be fairly easy to harvest and enrich using existing techniques, the new findings open the exciting possibility that the skin’s healing ability can be enhanced via delivery of regeneration-competent blood-derived progenitors to the site of the wound. As an immediate next step, an information-rich catalog of diverse wound fibroblasts will help form a platform for the team to begin identifying new sub-types of cells that enhance scarring, or promote repair toward scar-less skin regeneration. Additional contributors to this study were Priya Dedhia, Suoqin Jin, Rolando Ruiz-Vega, Dennis Ma, Yuchen Liu, Kosuke Yamaga, Olga Shestova, Denise Gay, Zaixin Yang, Kai Kessenbrock, Qing Nie and Warren Pear. The research received support from the National Institutes of Health, the National Science Foundation, the Simons Foundation and the Pew Charitable Trusts.
Newswise — Lawrenceville, NJ, USA—February 11, 2019—Value in Health, the official journal of ISPOR—the professional society for health economics and outcomes research—announced today the publication of an ISPOR scoping review showing that “medical nutrition” terminology is not consistently defined, relevant European and US regulations are infrequently cited, and economic evaluations are infrequently conducted. The report, “Medical Nutrition Terminology and Regulations in the United States and Europe—A Scoping Review: Report of the ISPOR Nutrition Economics Special Interest Group,” was published in the January 2019 issue of Value in Health. ISPOR’s Nutrition Economics Special Interest Group conducted a scoping review of scientific literature on European and US medical nutrition terminology and regulations to ascertain how: 1) medical nutrition terms are defined, 2) relevant regulations are applied, and 3) medical nutrition is economically evaluated in the United States and Europe. In total, 459 records were included in the analysis, of which 308 used medical nutrition terms. The review identified very few medical nutrition definitions, most of which were heterogeneous. The terms most frequently defined were malnutrition (58 records), enteral nutrition (9), undernutrition (7), and parenteral nutrition (5). Likewise, relevant regulations were infrequently cited; overall, less than 5% of the records referenced any medical nutrition regulation. Finally, just 34 of the 459 records reported some type of economic data, and only 19 contained a full or partial health economic evaluation. “The integral role that food and nutrients play in the etiology and progression of disease is pushing healthcare decision makers to consider the cost and value of nutrition interventions,” said author Karen Freijer, PhD, RDN, School for Public Health and Primary Care, Maastricht University, Maastricht, The Netherlands. “The current lack of consensus on medical nutrition terminology hampers research and analysis of its impact on health and economic outcomes in the management of disease- and condition-related nutrition therapy. To sustain value-based decisions within healthcare systems, establishing a common understanding of the terms and definitions surrounding medical nutrition is the critical first step to build the foundation of future nutrition economics research and evaluation of interventions.” The two major nutrition societies in Europe (ESPEN) and the United States (ASPEN) have prioritized, and are calling for, continuing constructive discussions to reach a consensus statement for the benefit of the global nutrition community. The authors note that the ISPOR Nutrition Economics Special Interest Group fully supports this ongoing initiative and emphasizes that adopting standardized medical nutrition terminology is essential to develop reliable and harmonized methodologies.
The use of MRI to determine heart function has been slow to catch on, but a study from Duke Health researchers shows that stress cardiac MRI not only diagnoses disease, but can also predict which cases are potentially fatal. Newswise — DURHAM, N.C. – The use of MRI to determine heart function has been slow to catch on, but a study from Duke Health researchers shows that stress cardiac MRI not only diagnoses disease, but can also predict which cases are potentially fatal. Results from a large, multi-center study suggest that cardiac magnetic resonance, or CMR, has potential as a non-invasive, non-toxic alternative to stress echocardiograms, catheterizations and stress nuclear exams in identifying the severity of coronary artery disease. The study appears online Feb. 8 in JAMA Cardiology. “We’ve known for some time that CMR is effective at diagnosing coronary artery disease, but it’s still not commonly used and represents less than one percent of stress tests used in this country,” said senior author Robert Judd, Ph.D., co-director of the Duke Cardiovascular Magnetic Resonance Center. “One of the impediments to broader use has been a lack of data on its predictive value -- something competing technologies have,” Judd said. “Our study provides some clarity, although direct comparisons between CMR and other technologies would be definitive.” Judd and colleagues analyzed data from more than 9,000 patients who underwent CMR at seven U.S. hospitals, encompassing up to 10 years of follow-up. For patients without any history of heart disease and at low risk based on traditional clinical criteria, those with an abnormal CMR scan were 3.4 times more likely to die compared to patients with a normal CMR scan. For the entire patient population, the researchers found a strong association between an abnormal stress CMR and mortality, even after adjusting for patient age, sex, and cardiac risk factors. “Noninvasive cardiac stress testing is a cornerstone in the clinical management of patients with known or suspected coronary artery disease,” Judd said, noting that CMR works as well or better than other exams at identifying heart wall motion, cell death and the presence of low blood flow. In addition, the technology does not require any radiation exposure, which is essential in nuclear stress tests that are by far the most commonly used in the U.S. “There are a number of reasons for the limited use of stress CMR, including availability of good quality laboratories, exclusion of patients who cannot undergo magnetization, and a lack of data on patient outcomes,” Judd said. “With the findings from this study suggesting that stress CMR is effective in predicting mortality, we provide a strong basis for a head-to-head study between stress CMR and other modalities.” In addition to Judd, study authors at Duke include Raymond J. Kim, Han W. Kim, Igor Klem, Elizabeth Jenista and Michele Parker. They were joined by John F. Heitner and Jean Ho of New York Presbyterian Brooklyn Methodist Hospital; Dipan J. Shah and Dany Debs of Houston Methodist DeBakey Heart & Vascular Center; Afshin Farzaneh-Far of the University of Illinois at Chicago; Venkateshwar Polsani of Piedmont Atlanta Hospital; Jiwon Kim and Jonathan Weinsaft of Weill Cornell Medical Center; Chetan Shenoy and Andrew Hughes of the University of Minnesota Medical Center; Preston Cargile of Heart Imaging Technologies; Robert O. Bonow of Northwestern University Feinberg School of Medicine The study received funding support from the National Heart, Lung, and Blood Institute, (R42 HL080843, R42 HL106864, R42 HL117397, R01 HL128278, and K23 HL132011). Judd and Raymond J. Kim have an equity interest in Heart Imaging Technologies.
Newswise — MADISON – Medicine was transformed in the 20th century by the discovery and development of antibiotics, the vast majority of which came from one source: soil bacteria. But we seem to have tapped out that supply. Resistance by disease-causing pathogens to existing antibiotics is increasing, endangering millions of lives and costing billions of dollars. New surveys of soil bacteria tend to turn up old chemicals. And few pharmaceutical companies are developing new antibiotic drugs. But the same class of bacteria that gave us many of our antibiotics, known as Streptomyces, makes a home not just in the soil but all over, including on insects. Cameron Currie, a University of Wisconsin–Madison professor of bacteriology, has shown that some of these insect-associated microbes provide their hosts with protection against infections, suggesting that insects and their microbiomes may be a rich new source of antibiotics for use in human medicine. So with a team of collaborators, Currie set out to test that idea, thousands of times over. In an exhaustive search of microbes from more than 1,400 insects collected from diverse environments across North and South America, Currie’s team found that insect-borne microbes often outperformed soil bacteria in stopping some of the most common and dangerous antibiotic-resistant pathogens. In their work, the scientists discovered a new antibiotic from a Brazilian fungus-farming ant, naming it cyphomycin. Cyphomycin was effective in lab tests against fungi resistant to most other antibiotics and combatted fungal infections without causing toxic side effects in a mouse model. The researchers have submitted a patent based on cyphomycin because of its effectiveness in these early tests, setting up the team to begin to do the significant additional work required before cyphomycin could be developed into a new drug used in the clinic. The study is the largest and most thorough to assess insect-associated microbes for antibiotic activity to date. The work was published Jan. 31 in the journal Nature Communications. The study was led by Currie lab graduate student Marc Chevrette with collaborators in the UW–Madison School of Pharmacy, the UW School of Medicine and Public Health and several other institutions in North and South America. Streptomyces evolved about 380 million years ago and have since diverged into many lineages, some of which are more commonly found in soil or associated with insects. That evolutionary distance means that insect-associated microbes have adapted to their own unique environmental contexts. “It follows that if you look in a different evolutionary context, you find new chemistry,” says Chevrette. To survey a large portion of insect diversity, the Currie team collected more than 2,500 species across all major groups of insects, including flies, ants and bees, moths and butterflies, beetles and more. About a third were collected in tropical landscapes, and another third from temperate climates, with the remainder from arctic or other regions. “We could collect 400 insects in a few days,” says Currie, whose own collecting assignment took him to Hawaii in winter. More than half of those insects harbored the right kinds of bacteria. In all, the insects provided more than 10,000 microbes to test. The team isolated another 7,000 strains from soil or plant sources. Then came the experiments — a lot of them. “The real power in our study is that we did it 50,000 times,” says Chevrette. Those 50,000 trials tested each microbe’s ability to inhibit the growth of 24 different bacteria and fungi, many of which, like methicillin-resistant Staphylococcus aureus, better known as MRSA, pose serious threats to human health. A greater proportion of insect-associated microbes were able to inhibit the growth of these bacterial or fungal targets than were microbes isolated from soil or plants. With Professor of Medical Microbiology David Andes from the UW School of Medicine and Public Health, the researchers tested several dozen promising microbe strains for their ability to fight infections in mice. Extracts from these microbes effectively killed both bacterial and fungal pathogens, and few demonstrated toxic side effects. As a further proof of concept, the team worked with School of Pharmacy professor Tim Bugni to purify cyphomycin and determine its chemical structure. Cyphomycin was able to treat infection in mice by Candida albicans, an opportunistic fungal pathogen that often infects immunocompromised people. Cyphomycin also showed low toxicity in mice. By demonstrating effective antimicrobial action and low toxicity in mice, the researchers have passed the first barrier to developing new antibiotics for clinical use in humans. But many promising drugs fail further along in development, which is why it is important to identify multiple candidate antibiotics in the early stages. Currie’s team isn’t surprised that insect-associated microbes are a promising source of novel antibiotics. For one, they say, insects may help select for antibiotics that are not toxic to animals. And because many insects rely on microbial antibiotics to combat ever-evolving pathogens in their own environment, they have likely selected for antibiotics that can overcome common resistance mechanisms. “The insects are doing the prospecting for us,” says Currie. This work was supported by the National Institutes of Health (grants U19 Al109673, U19 TW009872, and National Research Service Award T32 GM008505) and the National Science Foundation (grant MCB-0702025).
Newswise — Breakthrough research demonstrating that children with autism as young as 18 months can vastly improve their language, cognition and social skills with an early intervention developed by UC Davis Professor Sally Rogers has been replicated in a major new study. Rogers, a professor of Psychiatry and Behavioral Sciences at the MIND Institute, began work on a novel developmental approach to autism in Denver in 1981, and in partnership with her colleague and co-author Geraldine Dawson developed an approach to improving long-term outcomes for very young children. The Early Start Denver Model has since become a method used throughout the U.S. and around the world. But until now ESDM had not been tested in the most rigorous fashion − a multi-site randomized trial, comparing the approach with community-based autism interventions. The study, which appears today in Journal of the American Academy of Child and Adolescent Psychiatry, began in 2007 at three university sites around the country. The new research replicates an ESDM study published in 2010. Rogers emphasized that replication studies are rare and costly but critical to validate novel scientific findings. The new study found that children receiving intensive ESDM in their homes for an average of 15 hours per week made significantly greater language gains than did children in the community interventions, and this was true for both children with more severe delays and those with less. In addition to validating the efficacy of ESDM for language development, the study also found that children receiving services in the community settings made large gains in several areas. “The idea that little children with autism who are getting good treatment can make this much IQ and language gain means we should expect this from quality early-intervention experiences,” Rogers said. “These findings should raise families’ hopes a whole lot.” Pioneering autism treatment was a new idea What distinguishes ESDM from the more traditional, behavioral interventions used with children with autism is that it combines developmental and behavioral approaches and is carried out within in everyday routines. ESDM is built on moment-to-moment interactions that young children typically have with other people, especially their parents, and uses children’s interests and favorite activities to assure that social interaction is interesting and fun. “Unlike other approaches popular at the time that the Denver Model began, we used a typical preschool physical environment and focused on the learning opportunities that existed in social interactions between children and adults to accelerate children’s development,” Rogers said. “This was a new idea at the time.” In 2012, TIME magazine named ESDM one of the top 10 medical breakthroughs because their work demonstrated that brain function among young children with autism can normalize with effective early intervention in profound, enduring ways. For the current study 118 children with autism, ages 14 months to two years, were enrolled and randomly assigned to either ESDM or community interventions for 27 months. Children assigned to ESDM intervention received three months of weekly parent coaching followed by 24 months of one-on-one treatment about 15 hours per week in homes or daycare settings from supervised therapy assistants. Parents received coaching four hours monthly from a certified ESDM therapist. In the community setting, hours of treatment varied by site. What researchers found was that at two of the three sites, children receiving ESDM had significantly more language improvement than the children in the community interventions, and there was no significant difference in language gain at the third site between the two modalities. When results from all three sites were pooled, there was a significant advantage for the children in the ESDM group overall. “Language is the bridge to learning,” Rogers said. “Language is the door that opens up social communication and education and interactions with people in your community. It’s how you share with people. It’s a main vehicle for social interaction once you pass infancy.” Autism treatment in the community greatly improved over time The study also found that in terms of cognition and social skills, both the ESDM and community treatment groups made significant gains. Fortunately, Rogers said, laws requiring insurance coverage for early autism intervention and new knowledge about effective treatment have greatly improved community options for families seeking help for young children diagnosed with autism. Rogers said families with a child diagnosed with autism should take some comfort knowing that the early treatments now widely available do make a difference. “It says the autism scores at the time of diagnosis are just a starting point,” she said. “It says that the developmental paths and learning capacity of young children with autism are more plastic than we knew, and there are many ways to get learning opportunities to them.” In addition to Rogers, UC Davis authors on the study were Marie Rocha, Laurie Vismara and Meagan Talbott. Other co-authors on the study included: Annette Estes and Jessica Greenson of the University of Washington; Catherine Lord and Jamie Winter of Weill Cornell Medicine, Cornell University; Costanza Colombi of University of Michigan; Geraldine Dawson of Duke University, and Gerhard Hellemann of UCLA. This study was supported by individual Autism Speaks grants to Annette Estes and to Sally Rogers and by NIMH/NICHD award number R01 081757 as part of the Autism Centers of Excellence (ACE) Treatment Network, clinicaltrials.gov identifier NCT 00698997.
Newswise — ROCHESTER, Minn. — Kidney stones are a common and painful condition, with many sufferers experiencing recurrent episodes. Most people who pass an initial stone want to know their chances of future episodes, but this has not always been easy to predict. Now Mayo Clinic researchers are tracking the familiar characteristics of kidney stone formers in an online prediction tool that could help sufferers anticipate if they'll experience future episodes. The study was published in Mayo Clinic Proceedings. Using data obtained from the Rochester Epidemiology Project, a team of researchers explored a sampling of chronic kidney stone formers from Olmsted County between 1984 and 2017. Common features of patients who had recurrent stone events included younger age, male sex, a higher body mass index, history of pregnancy, and a family history of stones. Researchers also noted that stone recurrence tended to increase after each subsequent event, and the size and location of stones also associated with the risk of future episodes. By using these features to develop a Recurrence of Kidney Stone online prediction tool, researchers were able to improve upon known criteria for future stone formation. By entering information such as gender, race and an individual's kidney stone history, the tool can generate an estimate of recurrence. “Each of the risk factors we identified are entered into the model, which then calculates an estimate of the risk of h0aving another kidney stone in the next five or 10 years,” explains John Lieske, M.D., one of the study researchers. Updating the Recurrence of Kidney Stone model with data collected from the study has improved the tool's ability to predict subsequent events. Since the risk of stone recurrence varies depending on individual factors, this information can be useful for patients or caregivers when deciding how aggressively they want to adopt measures to reduce risk for stone recurrence. The tool, which is available online or as an app, also can be used in research studies to identify those patients most likely to have more kidney stone attacks. Data used in the Recurrence of Kidney Stone model were based on results from Olmsted County, Minnesota. These data will need to be validated in other parts of the country to establish whether the findings are translatable to other settings. Having a baseline knowledge of risk factors for stone recurrence and the potential for future episodes can be an incentive for individuals to modify lifestyle behaviors. By knowing the likelihood of future kidney stone episodes, Dr. Lieske notes that this could help encourage a patient's “enthusiasm for adopting dietary measures and/or starting drug regimens to prevent future attacks.” ###
Newswise — Although growing evidence supports the safety and effectiveness of an assortment of clinical interventions for critically ill patients known as the ABCDEF bundle, critical care providers often struggle with how to incorporate the various elements into clinical practice. The bundle integrates pain, sedation and delirium management with ventilator weaning, early mobility efforts and family engagement into a single collection of evidence-based best practices. According to the Society of Critical Care Medicine (SCCM), components of the ABCDEF bundle individually and collectively can help reduce delirium, improve pain management and reduce long-term consequences for adult intensive care unit (ICU) patients. SCCM received a grant from the Gordon and Betty More Foundation to support the ICU Liberation ABCDEF Bundle Improvement Collaborative, a 20-month, nationwide quality improvement initiative designed to promote widespread dissemination and implementation of the bundle. From 2015 to 2016, 68 adult and nine pediatric hospitals from 29 states and Puerto Rico participated in the Collaborative, representing academic, community and federal hospitals from both rural and urban areas. An interprofessional team with expertise in ABCDEF bundle implementation and quality improvement served as faculty for the Collaborative, helping critical care providers at individual sites through the adoption of the bundle in their ICUs. Through in-person meetings and email discussions, the Collaborative identified the most common and challenging barriers to bundle implementation experienced by participating sites. Two articles in the February issue of Critical Care Nurse (CCN) provide practical advice from these leading experts on effective strategies for overcoming the barriers. In “Implementing the ABCDEF Bundle: Top 8 Questions Asked During the ICU Liberation ABCDEF Bundle Improvement Collaborative,” the team describes the most frequently asked questions and provides practical advice for other institutions implementing the bundle. The questions cover each element of the ABCDEF bundle, as well as teamwork and process improvement. A second article, “Common Challenges to Effective ABCDEF Bundle Implementation: The ICU Liberation Campaign Experience,” discusses some of the most challenging implementation issues that Collaborative teams experienced and recommends specific strategies to overcome the barriers. “Each member of the ICU team, including patients and their families, offers unique contributions that are essential to implementing the ABCDEF bundle and delivering patient-centered care in the ICU,” said Joanna Stollings, PharmD, a Collaborative faculty member and co-author of the articles. She is a clinical pharmacist in the department of pharmaceutical services, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee. “Critical care staff can use the strategies provided by the Collaborative to facilitate their efforts to adopt the bundle.” SCCM offers an online resource library as part of its ICU Liberation initiative to encourage widespread use of the ABCDEF bundle. Additional clinical resources related to the ABCDEF bundle are available from the American Association of Critical-Care Nurses (AACN), which publishes CCN. Clinicians should also refer to the recently published 2018 SCCM Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS), as they boost ABCDEF bundle implementation efforts. As part of its AACN Critical Care Webinar Series, AACN hosts a webinar Feb. 14 to present the PADIS guidelines’ recommendations on the management of patients with pain, agitation and delirium, and the impact on clinical practice. Brenda Pun, DNP, RN, an advanced practice nurse at VUMC and one of the Collaborative’s faculty members, will lead the webinar. As AACN’s bimonthly clinical practice journal for high-acuity and critical care nurses, CCN is a trusted source of information related to the bedside care of critically and acutely ill patients. Access the article abstract and full-text PDF by visiting the CCN website at http://ccn.aacnjournals.org. About Critical Care Nurse: Critical Care Nurse (CCN), a bimonthly clinical practice journal published by the American Association of Critical-Care Nurses, provides current, relevant and useful information about the bedside care of critically and acutely ill patients. The award-winning journal also offers columns on traditional and emerging issues across the spectrum of critical care, keeping critical care nurses informed on topics that affect their practice in high-acuity, progressive and critical care settings. CCN enjoys a circulation of more than 120,000 and can be accessed at http://ccn.aacnjournals.org/. About the American Association of Critical-Care Nurses: Founded in 1969 with 400 members, the American Association of Critical-Care Nurses (AACN) is now the world’s largest specialty nursing organization. In 2019, AACN celebrates 50 years of acute and critical care nursing excellence, serving more than 120,000 members and over 200 chapters in the United States. The organization remains committed to its vision of creating a healthcare system driven by the needs of patients and their families in which acute and critical care nurses make their optimal contribution. During its 50th anniversary year, AACN continues to salute and celebrate all that nurses have accomplished over the last half century, while honoring their past, present and future impact on the evolution of high-acuity and critical care nursing. American Association of Critical-Care Nurses, 101 Columbia, Aliso Viejo, CA 92656-4109; 949-362-2000; www.aacn.org; facebook.com/aacnface; twitter.com/aacnme
Newswise — Regular use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may help some patients with head and neck cancer survive the disease, according to a study led by Professor Jennifer Grandis at the University of California, San Francisco. The study, which will be published January 25 in the Journal of Experimental Medicine, indicates that NSAIDs are effective in patients with mutations in a gene called PIK3CA, and the researchers suggest this is because NSAIDs lower the levels of an inflammatory molecule called prostaglandin E2. The researchers note, however, that they are not yet able to make any specific recommendations about the type, timing, or dosage of NSAIDs such patients should take, and that their results need to be corroborated by a prospective clinical trial. Head and neck squamous cell carcinoma (HNSCC) accounts for about 4% of all cancers in the US and continues to have high rates of patient mortality. Risk factors for HNSCC include smoking, alcohol use, and human papillomavirus infection, but several studies have shown that regular use of aspirin can reduce the risk of developing the disease. However, whether aspirin or other NSAIDs can promote the survival of patients who have already developed HNSCC is unclear; studies investigating this question have so far produced conflicting results. One possibility is that NSAIDs are only effective against some types of HNSCC. Around 35% of HNSCC tumors carry mutations that activate the PIK3CA gene, which encodes the catalytic subunit of a key signaling enzyme called PI3Ka. The team of researchers led by Dr. Grandis investigated whether regular NSAID use specifically improved the survival of HNSCC patients with alterations in the PIK3CA gene. The team, which also included researchers from the University of Pittsburgh School of Medicine and the University of Arizona, analyzed a group of 266 HNSCC patients who had had their tumors surgically removed and, in most cases, were then treated with adjuvant chemotherapy and/or radiotherapy. Patients without any alterations in their PIK3CA gene were no better off if they also took NSAIDs on a regular basis (defined as taking two or more doses per week for at least six months). By contrast, regular NSAID usage dramatically enhanced the survival of patients whose PIK3CA gene was mutated and/or amplified. Among these patients, NSAIDs increased the overall five-year survival rate from 45% to 78%. NSAIDs also reduced the growth of tumors in mice injected with cancer cells harboring a mutant PIK3CAgene. By analyzing these mice, Grandis and colleagues found that NSAIDs likely inhibit tumor growth by reducing the production of prostaglandin E2. This proinflammatory molecule has been implicated in a variety of cancers and can be induced by the PI3Ka signaling pathway. NSAIDs may therefore also be effective against a variety of cancers that contain activating mutations in the PIK3CA gene. Indeed, previous studies have shown that regular aspirin usage can aid the survival of colorectal cancer patients carrying mutated PIK3CA. “The present study is the first to demonstrate that regular NSAID usage confers a significant clinical advantage in patients with PIK3CA-altered HNSCC,” Grandis says. “Inconsistencies in the type, timing, and dosages of NSAIDs taken by patients in this study limit our ability to make specific therapeutic recommendations. But the magnitude of the apparent advantage, especially given the marked morbidity and mortality of this disease, warrants further study in a prospective, randomized clinical trial.” Hedberg et al., 2019. J. Exp. Med. http://jem.rupress.org/cgi/doi/10.1084/jem.20181936?PR
Newswise — Newborn babies are born with the innate skills needed to pick out words from language, a new study published in Developmental Science reveals. Before infants can learn words, they must identify those words in continuous speech. Yet, the speech signal lacks obvious boundary markers, which poses a potential problem for language acquisition. Studies have found that by the middle of the first year, infants seem to have solved this problem, but it is unknown if segmentation abilities are present from birth, or if they only emerge after sufficient language exposure and/or brain maturation. Near-Infrared Spectroscopy An international team of researchers from the University of Liverpool, SISSA in Italy, the Neurospin Centre in France and The University of Manchester conducted experiments to find the cues crucial for the segmentation of human speech. The researchers played the infants a three-and-a-half minute audio clip in which four meaningless words, were buried in a stream of syllables. Using a painless technique called Near-Infrared Spectroscopy, which shines red light into the brain, they were able to measure how much was absorbed, telling them which parts of the brain were active. 'Key Insight' The researchers discovered two mechanisms in three-day-old infants, which give them the skills to pick out words in a stream of sounds. The first mechanism is known as prosody, the melody of language, allow us to recognise when a word starts and stops. The second is called the statistics of language, which describes how we compute the frequency of when sounds in a word come together. The discovery provides a key insight into a first step to learning language. Important tools Dr Alissa Ferry, University of Manchester, said: "We think this study highlights how sentient newborn babies really are and how much information they are absorbing. That's quite important for new parents and gives them some insight into how their baby is listening to them." Dr Perrine Brusini, University of Liverpool, said: "We then had the infants listen to individual words and found that their brains responded differently to the words that they heard than to slightly different words. "This showed that even from birth infants can pick out individual words from language." Dr Ana Flò, Neurospin, said: "Language in incredibly complicated and this study is about understanding how infants try to make sense of it when they first hear it. We often think of language as being made up of words, but words often blur together when we talk. So one of the first steps to learn language is to pick out the words. "Our study shows that at just three days old, without understanding what it means, they are able pick out individual words from speech. And we have identified two important tools that we are almost certainly born with, that gives them the ability to do this."
Newswise — Researchers from the National Institutes of Health have discovered that antibodies that may form the basis of a universal flu vaccine inhibit a second viral protein in addition to the one that they bind. The study, to be published January 25 in the Journal of Experimental Medicine, reveals that antibodies that recognize the viral surface protein hemagglutinin can also inhibit the viral neuraminidase, and that this enhances antibody neutralization of the virus and the activation of innate immune cells with anti-viral activity. Hemagglutinin and neuraminidase are yin-yang proteins present on the surface of the influenza virus. The former mediates virion attachment and fusion with host cell membranes, while the latter is an enzyme that releases budding progeny virions from the cell surface that remain attached via the hemagglutinin binding. Hemagglutinin consists of a head domain that contains the receptor binding site that attaches to host cell membranes and a stem domain that connects the head to the virion membrane. Current flu vaccines induce antibodies that recognize the hemagglutinin head and inhibit its ability to mediate viral entry. But the hemagglutinin head undergoes rapid mutation to escape existing antibodies. This generates vaccine–resistant strains of the influenza virus each year, necessitating the yearly mad dash to create a matched vaccine. The hemagglutinin stem domain, in contrast, is far more resistant to mutations, providing a target for universal flu vaccines, as has been shown by dozens of studies in animal models. “Hemagglutinin stem-specific antibodies are perhaps the most promising approach for improving the duration and effectiveness of influenza vaccination,” write the authors of the study, which was led by Jonathan W. Yewdell, a senior investigator at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “It is therefore critical to better understand how anti-stem antibodies provide protection from the virus.” Stem-binding antibodies can block viral entry into host cells by inhibiting hemagglutinin cell fusion activity, but as Yewdell’s lab reports, they also inhibit the release of newly replicated virions by blocking neuraminidase molecules in close proximity to hemagglutinin on the virion. Experiments in mice confirmed that the ability of anti-stem antibodies to inhibit neuraminidase enabled animals to better survive a severe influenza infection. Yewdell and colleagues think that this effect may be largely due to the role that neuraminidase normally plays in preventing the activation of innate immune cells with anti-viral activity. In support of this idea, the researchers found that the FDA-approved neuraminidase inhibitor oseltamivir (Tamiflu) further boosted the ability of anti-stem antibodies to activate immune cells exposed to influenza virus. “The ability of neuraminidase inhibitors to enhance… immune cell activation [by anti-stem antibodies] bound to viruses or infected cells suggests the possible clinical synergy between neuraminidase inhibitors and [anti-stem antibodies] in humans,” the authors write. In addition, this new understanding of how anti-stem antibodies exert their protective effects should aid the design of universal flu vaccines targeting the hemagglutinin stem domain. Kosik et al., 2019. J. Exp. Med. http://jem.rupress.org/cgi/doi/10.1084/jem.20181624?PR