Newswise — White blood cells known as B cells have been shown to be effective for predicting which cancer patients will respond to immune checkpoint blockade (ICB) therapy, according to a study at The University of Texas MD Anderson Cancer Center. Study results will be presented April 2 at the AACR Annual Meeting 2019in Atlanta. The study, led by Jennifer Wargo, M.D., professor in the Surgical Oncology and Genomic Medicine, found that some B cells with unique characteristics predicted response and may be contributing mechanistically to the immune system’s response. The B cells had activated effector phenotypes and were located within lymphoid formations found at the tumor site, known as tertiary lymphoid structures (TLS). The researchers looked at samples from metastatic melanoma and kidney cancer patients who had received ICB as their initial treatment. The B cells may be impacting the immune system’s response through secretion of antibodies and/or by processing and delivering antigens to white blood cell subtypes called T lymphocytes. “This is an exciting and emerging area of study that appears to hold promise for more accurately understanding which patients are most likely to be treated effectively with ICB therapy, and it also could help us identify new therapeutic targets.” said Wargo. “We are able to demonstrate through single-cell RNA sequencing that switched memory B cells and plasma cells were significantly associated with ICB response in a cohort of metastatic melanoma.” While cytotoxic T-cell markers, PD-L1, and mutational burden have been previously identified as biomarkers of response to ICB, there is a growing appreciation of B cells as biomarkers mediators of response, although B cells have also been linked to negative cancer outcomes. “Whole transcriptomic analysis of the cohort of melanoma patients receiving ICB initially revealed that most differentially expressed genes by response were related to B cells,” said Wargo. “In further investigation of specific characteristics of B cells located within the tumor, we identified naive, class-switched and unswitched memory B cells, and plasma cell-like populations.” Class-switch references a B cell’s ability to change production of an antibody from one class to another. The team found higher frequencies of class-switched memory B and plasma-like cells in patients who responded to ICB. Patients who did not respond to ICB had higher levels of naïve B cells which have not yet been activated for a designated purpose. “We don’t have a complete understanding of how these B cells contribute to therapeutic response, but we and others are working on this, and we hope this research will stimulate additional study in this area,” said Wargo. “There is still much to learn and the strongest gains are made through collaboration. It is something we owe to our patients.” MD Anderson study team participants included Sangeetha Reddy, M.D.; Beth Helmink, M.D., Ph.D.; Vancheswaran Gopalakrishnan, M.D.; Elizabeth Burton; and Jeffrey Gershenwald, M.D.; all of Surgical Oncology; Jianjun Gao, M.D., Ph.D.; and Padmanee Sharma, M.D., Ph.D., of Genitourinary Medical Oncology; Shoaojun Zhang, Ph.D.; Guangchun Han, Ph.D.; and Linghua Wang, Ph.D.; of Genomic Medicine; Jorge Blando, D.V.M.; Wenbin Liu; Hao Zhao, D.Phil.; and James Allison, Ph.D.; of Immunology; Hussein Tawbi, M.D., Ph.D.; Rodaba Amaria, M.D.; and Michael Davies, M.D., Ph.D., of Melanoma Medical Oncology; Michael Tetzlaff, M.D., Ph.D., of Pathology; and Rafet Basar, M.D.; and Katy Rezvani, M.D., Ph.D., of Stem Cell Transplantation and Cellular Therapy. The Broad Institute of the Massachusetts Institute of Technology also participated in the study. The study was funded by the Parker Institute for Cancer Immunotherapy, and was also supported with funding from the Melanoma Moon Shot™, part of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives. A complete list of disclosures can be found in the AACR abstract.
Newswise — People under age 50 with hearing loss misuse prescription opioids at twice the rate of their hearing peers, and are also more likely to misuse alcohol and other drugs, a new national study finds. This means that health care providers may need to take special care when treating pain and mental health conditions in deaf and hard-of-hearing young adults, the researchers say. Writing in the April issue of the American Journal of Preventive Medicine, a team from the University of Michigan and VA Ann Arbor Healthcare System describe their findings from data on 86,186 adults who took part in the National Survey on Drug Use and Health. In all, adults under 50 with hearing loss were more likely than others in their age group to have a substance use disorder of any kind, while those over 50 with hearing loss did not differ from their peers in rates of substance issues. Even after the researchers adjusted for differences in social, economic and mental health between the hearing and hard-of-hearing populations, the differences remained. Adults under age 35 with a hearing loss were two and a half times more likely to have a prescription opioid use disorder. Those between age 35 and 49 who had hearing loss were nearly twice as likely as their hearing peers to have disorders related to both prescription opioids and alcohol. Michael McKee, M.D., M.P.H., led the research effort after noticing that that a disproportionate share of his younger patients with hearing loss were struggling with substance use disorders. McKee runs the Deaf Health Clinic that provides primary care and mental health care to d/Deaf and hard-of-hearing patients of Michigan Medicine, U-M’s academic medical center. “Hearing loss is connected with a variety of health problems, including mental and physical health, that may place these individuals at risk for pain disorders,” says McKee. “Also, the marginalizing effects of hearing loss, such as social isolation, may be creating higher rates of substance use disorders too.” For those whose health care providers know of their hearing loss, McKee suspects that the higher rate of prescription opioid use disorder may stem from a higher rate of being placed on controlled substances to quickly address pain issues, perhaps because of communication barriers. “It may be easier to write a prescription rather than engage in complex patient-provider communication between a hearing provider and non-hearing patient,” he says. But the research suggests that part of the issue may be lack of awareness by health care providers of their younger patients’ degree of hearing loss. In all, five percent of adults of all ages taking part in the survey said they had serious hearing loss or were deaf. The proportion ranged from 1.5 percent of those under age 35, to 2.2 percent of those between 35 and 49, to 9.4 percent of those over 50. McKee, a U-M Department of Family Medicine physician who uses a cochlear implant to offset his own hearing loss, says health care providers may be more attuned to potential communication and prescription concerns with older patients. This would mean they would be more likely to avoid many of the prescription use disorders seen in the other two age categories. “We need to first inquire and ensure effective and accessible communication with our patients. We need to be willing to engage in a dialogue to explore the root of their pain/mental health issues rather than just dispensing a prescription that may lead to dependency or addiction,” he says. This means providers should use “universal communication precautions” – approaching each patient without assumptions about their communication abilities, assessing for hearing loss and other communication-related issues, and determining how to accommodate each patient. McKee also notes that lack of access to addiction-related care for deaf and hard-of-hearing patients may play a role. McKee and several co-authors are faculty in the U-M Medical School and members of the U-M Institute for Healthcare Policy and Innovation. They include disability researcher Michelle Meade, Ph.D. of the Department of Physical Medicine and Rehabilitation, chair of Family Medicine Philip Zazove, M.D. and Mark Ilgen, Ph.D., director of the U-M Addiction Treatment Service. The research team also included Haylie Stewart and Mary Jannausch from the U-M Department of Psychiatry and VA Center for Clinical Management and Research, of which Ilgen is also a member.
CDC data confirm: Progress in HIV prevention has stalled Need for immediate action —‘Ending the Epidemic: A Plan for America’ The dramatic decline in annual HIV infections has stopped and new infections have stabilized in recent years, according to a CDC report published today. The report provides the most recent data on HIV trends in America from 2010 to 2016. It shows that after about five years of substantial declines, the number of HIV infections began to level off in 2013 at about 39,000 infections per year. “Now is the time for our Nation to take bold action. We strongly support President Trump’s plan to end the HIV epidemic in America,” said CDC Director Robert R. Redfield, M.D. “We must move beyond the status quo to end the HIV epidemic in America.” The ‘Ending the HIV Epidemic’ Initiative During his State of the Union address to the nation on Feb. 5, President Trump called for support of a national planExternal to end the HIV epidemic in America that is built upon four key strategies, including: Diagnosing HIV as early as possible after infection. Treating HIV rapidly and effectively to achieve sustained viral suppression. Protecting people at risk for HIV using proven prevention approaches like pre-exposure prophylaxis (PrEP), a daily pill to prevent HIV. Responding rapidly to growing HIV clusters to stop new infections. The proposed initiative is designed to rapidly increase use of these strategies in the 48 counties with the highest HIV burden, as well as in Washington, D.C.; San Juan, Puerto Rico; and seven states with a disproportionate rural HIV burden. The goal is to reduce new HIV infections by 90 percent over 10 years. (For more details: HIV.govExternal.) “We have an historic opportunity to improve the precision of prevention,” said Jonathan Mermin, M.D., M.P.H., director, CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention. “This infusion of resources will finally relegate America’s HIV epidemic to the pages of history. New HIV Infections in America In addition to the overall trend, the new report examines HIV infections among multiple subgroups. Data indicate that annual HIV infections declined in some populations, but increased in others. CDC estimates that from 2010 to 2016, annual HIV infections: Remained stable among gay and bisexual men, who continue to account for the largest portion (about 70 percent) of new infections. However, trends varied by race/ethnicity and age: By race/ethnicity, infections remained stable among black gay and bisexual men; increased 30 percent among Latino gay and bisexual men; and decreased 16 percent among white gay and bisexual men. By race/ethnicity and age, infections decreased more than 30 percent among black gay and bisexual males ages 13 to 24; remained stable among Latino gay and bisexual males ages 13 to 24; and increased about 65 percent among both black and Latino gay and bisexual males ages 25 to 34. Decreased about 17 percent among heterosexual men and women combined, including a 15 percent decrease among heterosexual African American women. Decreased 30 percent among people who inject drugs, but appear to have stabilized in more recent years. CDC estimates that the decline in HIV infections has plateaued because effective HIV prevention and treatment are not adequately reaching those who could most benefit from them. These gaps remain particularly troublesome in rural areas and in the South and among disproportionately affected populations like African-Americans and Latinos. “After a decades-long struggle, the path to eliminate America’s HIV epidemic is clear,” says Eugene McCray, M.D., director of CDC’s Division of HIV/AIDS Prevention. “Expanding efforts across the country will close gaps, overcome threats, and turn around troublesome trends.” HIV Prevention that Works Some intensified local efforts to prevent HIV have already proven effective. For example, urban areas like New York and Washington, D.C., have developed and enacted plans to eliminate their local HIV epidemics — and they are seeing the results of those commitments. New HIV infections decreased about 23 percent in New York and about 40 percent in Washington, D.C., from 2010 to 2016. CDC provides funds to state health departments and some large local health departments and community-based organizations to deliver interventions proven to reduce HIV infections. Click here for more information about CDC’s approach to HIV prevention. The new initiative would supplement and accelerate these efforts over the next 10 years.
Newswise — By sequencing the entire genomes of tumor cells from six people with a rare cancer of the nose and sinus cavity, Johns Hopkins researchers report they unexpectedly found the same genetic change¾one in a gene involved in muscle formation¾in five of the tumors. “In terms of research linking genetic alterations to cancers, this is a true mountain and not a molehill,” says Gary Gallia, M.D., Ph.D., associate professor of neurosurgery at the Johns Hopkins University School of Medicine. “It’s fairly rare that a single gene is tied so tightly to the same cancers in unrelated people.” In a report on their findings, published Dec. 21, 2018, in Nature Communications, the researchers say the deletions they identified in a gene that codes for dystrophin, a rod-shaped protein that helps anchor muscle fibers in place, were found in olfactory neuroblastoma cells. Olfactory neuroblastomas make up just 6 percent of all sinus and nasal cancers, with a prevalence rate of one person out of every 2.5 million. Nationwide, that translates to about 100 to 200 diagnosed cases each year. Johns Hopkins Medicine’s neurosurgery skull base center is among the most experienced in treating patients with olfactory neuroblastoma. The center also has a robust supply of tissue samples from these tumors. The researchers say their findings contribute not only to a better understanding of the cause of these cancers, but also to the potential for creating animal and cell models for further study and development of treatments that target the tumor’s genetic roots. “Now that we believe we know the genetic cause of olfactory neuroblastoma, we can devise ways to disrupt the cancer, learn how it forms and explore new ways to treat it,” says Chetan Bettegowda, M.D., Ph.D.,associate professor of neurosurgery at the Johns Hopkins University School of Medicine and director of the Johns Hopkins meningioma center. “This was really an unexpected but fruitful finding.” Bettegowda says their finding was unexpected because perceptions of nasal and sinus tissue don’t immediately bring to mind a dominant role for muscle tissues. But, among geneticists, he says, it’s well known that many developmental genes that help form the tissues of the human body are multipurpose. For their study, the researchers first sequenced the tumor and matched normal DNA of nine men and two women with olfactory neuroblastoma taken from patients treated at Johns Hopkins over seven years. The patients ranged in age from 33 to 69. The researchers sequenced the parts of the genomes that make up the genes and not the spaces between the genes. Although they found two tumor samples had mutations in a large gene that makes the protein Titan, the researchers were unsure if these mutations may have contributed to formation of the cancer, as they didn’t see much else in common among the samples. Next, they chose six of these samples at random and did whole genome sequencing that looks at the DNA that makes up the genes and the DNA between the genes. This time they found that five of the six samples had deletions on the X chromosome, and in every case, the deleted portion of DNA spanned the gene DMD, which codes for the protein dystrophin, one of the genes implicated in muscular dystrophy. They then reexamined the original tumor samples, as well as a few others, with other techniques to look for deletions in dystrophin. In total, they found 12 out of 14 tumors had deletions in the DMD gene. In one tumor that didn’t have a DMD deletion, they found a deletion in another muscular dystrophy gene: LAMA2. Dystrophin is one of the longest genes in the human genome, and has 79 pieces of DNA interspersed with bits that don’t code for the gene. Because of the gene’s large size, if part of a chromosome in which it resides is deleted or rearranged, it’s statistically more likely to interrupt a large gene like dystrophin. The researchers aren’t sure if the dystrophin protein is made in the olfactory neuroblastoma or if a shortened mutated form messes up the inner workings of the cells that form the tumor. These are experiments for future studies, they say. The researchers still also don’t know what kind of cells the cancer originates from, although they are thought to arise from the neuroepithelium—the lining—of the sinuses at the point where the smell nerves poke through. As for whether their findings point to potential new therapies for this cancer, Bettegowda says, “Some low-hanging fruit could be to test certain therapies in the lab that have been tried in people with muscular dystrophy. Although those therapies have failed in treating muscles dystrophies, these conditions affect every cell in the body. But this cancer is found in one specific location, so the treatments might have a better chance of finding a target.” Typical signs of olfactory neuroblastoma are congestion, sinusitis, loss of sense of smell and nosebleeds. Other authors include Ming Zhang, Christine Hann, Alison Klein, Qing Wang, Bert Vogelstein, Kenneth Kinzler and Nickolas Papadopoulos of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Yi Ning, Michael Haffner, Denise Batista, Ralph Hruban, Masaru Ishii, Douglas Reh, Lisa Rooper, Rafael Tamargo, Tara Williamson, Tianna Zhao and Alan Meeker of Johns Hopkins; Zev Binder of the University of Pennsylvania; Justin Bishop of the University of Texas Southwestern Medical Center; Vafi Salmasi of Stanford University; Ying Zou of the University of Maryland and Nishant Agrawal of University of Chicago. The research was supported by the Virginia and D.K. Ludwig Fund for Cancer Research, the Sol Goldman Sequencing Facility at Johns Hopkins, the Johns Hopkins Clinician Scientist Career Development Award, the Burroughs Wellcome Fund Career Awards for Medical Scientists, the Doris Duke Charitable Foundation (2014107), the Department of Neurosurgery at Johns Hopkins and the National Cancer Institute (P50- CA062924). COI: Papadopoulos, Kinzler and Vogelstein are founders of Personal Genome Diagnostics and PapGene. Kinzler and Vogelstein are members of the scientific advisory board of Sysmex Inostics. Vogelstein is a member of the scientific advisory boards of Morphotek and Exelixis. These companies and others have licensed technologies from Johns Hopkins, and Papadopoulos, Kinzler and Vogelstein receive equity or royalties from these licenses.
Newswise — Radiologists quickly learn to read 3D mammography more accurately than they read standard 2D mammograms, a first-of-its-kind study by a UC Davis researcher has found. Published today in Radiology, the study led by Diana Miglioretti found that radiologists who interpret traditional mammograms, which are two-dimensional, required little start up time for transitioning to reading digital breast tomosynthesis (DBT), or 3D mammography, with improved screening accuracy. Researchers found radiologists recalled patients for additional testing at a lower rate on DBT than they did on 2D mammography, without sacrificing cancer detection. A patient may be recalled if there is a suspicious finding on the screening examination that requires follow-up imaging and possibly biopsy to determine if it is cancer. Three-dimensional views taken as part of a DBT screening help the radiologist confirm that some findings on 2D images are not cancer and so fewer patients have to be recalled. These improvements were seen regardless of the patient’s breast density. “We found that patients with or without dense breasts benefit from lower recall rates with 3D mammography and there is no trade off with cancer detection,” said Miglioretti, dean’s professor of biostatistics in the UC Davis Department of Public Health Sciences. “In fact, we were surprised to find that improvements in recall rates were larger in women without dense breasts.” Broad range and large number of radiologists sampled The study included data from 104 radiologists from 53 facilities in five U.S. states, collected by the Breast Cancer Surveillance Consortium (BCSC) to evaluate whether radiologists experience a learning curve for 3D mammography interpretive performance. The study is the largest of its kind and represented a broad range of radiology centers and providers. It is novel because it tracked radiologists’ performance over time as they transitioned from digital mammography to DBT. DBT takes multiple X-ray images of each breast from many angles which are then computer assembled into a three-dimensional image of the breast that the radiologist can scroll through. The U.S. Food and Drug Administration requires only eight hours of additional training for qualified radiologists to be able to interpret DBT studies. Researchers wondered if there was a learning curve associated with the interpretive performance of this new technology and if any improvements are sustained by radiologists over time. “We found both breast imaging subspecialists and general radiologists improved their screening performance when they switched from 2D to 3D mammography,” said Miglioretti. “These improvements were sustained for at least two years after adoption of the new technology.” Most women in the U.S. do not have their mammograms interpreted by a breast imaging subspecialist, nor do they have access to academic medical centers. The study evaluated radiologists with a mix of experience at both academic and nonacademic facilities. Both breast imaging subspecialists and general radiologists improved their interpretive performance quickly after adopting DBT, with lower recall rates and similar cancer detection rates as for digital mammography. “Women who want to reduce their chances of being recalled for additional testing may want to ask for digital breast tomosynthesis at their next screening exam,” said Miglioretti. Other collaborating researchers included Linn Abraham and Diana S.M. Buist, Kaiser Permanente Washington Health Research Institute; Christoph I. Lee, University of Washington; Sally Herschorn and Brian L. Sprague, University of Vermont; Louise M. Henderson, UNC Chapel Hill; Anna N.A. Tosteson, Dartmouth University; Karla Kerlikowske, UCSF. This research was supported by a Patient-Centered Outcomes Research Institute Program Award (PCS-1504-30370). Data collection was additionally supported by the Agency for Healthcare Research and Quality (R01 HS018366-01A1); National Cancer Institute (P01CA154292, U54CA163303); and the University of Vermont Cancer Center (Lake Champlain Cancer Research Organization grant 032800). Dr .Lee was supported by the American Cancer Society (126947-MRSG-1416001CPHPS).
Newswise — A surgeon sometimes moves from one surgery to the next before the first one is completed, leaving junior surgeons, residents and physician assistants to complete the noncritical portions of the procedure. The practice happens tens of thousands of times per year, but one might wonder: Are such overlapping operations safe? For the most part they are, but with two important exceptions, according to research by investigators at Harvard Medical School and Stanford University published Feb. 26 in JAMA and thought to be one of the most comprehensive analyses on the subject to date. The results, based on a comparison of outcomes from more than 60,000 surgical procedures, reveal that overall, overlapping surgeries do not increase the risk for post-surgical complications and patient death in the immediate aftermath of the procedure. However, there were two important exceptions. Patients deemed high risk—those with a relatively high predicted probability of complications from surgery, due to age and preexisting medical conditions—as well as patients undergoing coronary artery bypass experienced higher mortality and complication rates during overlapping surgeries. Additionally, overlapping procedures ran about a half hour longer on average than nonoverlapping procedures, the study found. “For most surgeries, and most patients, our findings should be reassuring,” said Anupam Jena, the Ruth L. Newhouse associate professor of health care policy in the Blavatnik Institute at Harvard Medical School and an internal medicine physician at Massachusetts General Hospital. “But for certain types of procedures and certain patients, the evidence suggests that we need to be thoughtful about whether a particular individual is a good candidate for overlapping surgery.” Jena was senior author of the study. As with any treatment, careful patient selection and an individualized approach based on the patient’s risk profile and preexisting conditions are critical, the researchers added. “As with anything else in medicine, one size does not fit all,” Jena said. Additionally, the investigators caution, the study was designed to capture only mortality and complication rates during the brief hospitalization period following surgery. It was not equipped to measure the long-term mortality and complications among patients once they were discharged. The mortality rate was 1.6 percent for patients undergoing nonoverlapping surgeries, compared with 1.9 percent among patients undergoing overlapping procedures. Postoperative complications occurred in 11.8 percent of patients undergoing nonoverlapping procedures, compared with 12.8 percent among those undergoing overlapping surgeries. Overlapping surgeries ran notably longer—204 minutes, compared with 173 minutes for nonoverlapping procedures. For high-risk patients, the mortality rate was 5.8 percent for patients undergoing overlapping surgeries, compared with 4.7 percent among patients undergoing nonoverlapping procedures. The complication rate was 29.2 percent for patients undergoing overlapping surgeries, compared with 27 percent among patients undergoing nonoverlapping procedures. For patients undergoing coronary artery bypass graft surgery, the mortality rate was 4 percent in surgeries with overlap versus 2.2 percent in surgeries without overlap. Complication rates were also higher in coronary artery bypass graft surgeries that involved overlap. The study analyzed outcomes among 66,430 patients, ages 18 to 90, undergoing eight common procedures at eight medical centers across the United States between 2010 and 2018. The procedures included knee and hip repairs, spinal surgeries, brain surgeries and coronary artery bypass grafting, a type of cardiac surgery to restore blood flow to the heart. Previous studies of overlapping surgeries tended to have more limited scope of analysis, the researchers said. For example, some focused on a single type of surgery or on results at a single hospital. In the current study, the authors used a national anesthesia registry to look at the start and end times of surgeries by individual surgeons so they could distinguish consecutive and overlapping surgeries. This enabled the researchers to tease out differences in outcomes for individual surgeons when they were performing one surgery at a time versus performing overlapping surgeries. By contrast, previous studies have compared overall outcomes, which may mask differences across individual operators. It is important to remember that overlapping surgeries have clear advantages, the researchers said, including maximizing the use of top surgeons and busy operating rooms, increasing patient access to necessary care and providing crucial training experience for junior surgeons. However, the researchers cautioned, such benefits must be weighed carefully against any potential risk to patients. Although overlapping surgeries are deemed generally safe, critics have suggested definitive evidence is lacking. The possibility of overlapping surgeries and any potential risks associated with a given patient or procedure should be disclosed to patients, who should feel empowered to ask whether their surgeon will be operating on other patients simultaneously and whether they are a good candidate for overlapping surgery. “Patient trust and patient empowerment should be paramount,” Jena said. “While the overall findings of the study suggest that overlapping surgeries appear to be safe, we found evidence that this may not be true for all patients and all procedures,” said the study’s lead author, Eric Sun, assistant professor in the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University. “Improving efficiencies and providing training opportunities should never come at the cost of patient safety, and we need good evidence to guide us as we make decisions about surgery, both as a matter of policy and as a matter of individual patient care.” Researchers from the University of Michigan and the University of Pennsylvania also contributed to this paper.This research was supported with funds from the Office of the Director, National Institutes of Health (NIH Early Independence Award, Grant 1DP5OD017897) and to the National Institute on Drug Abuse (K08DA042314). Relevant disclosures:Jena reports receiving consulting fees unrelated to this work from Pfizer, Hill-Rom Services, Bristol-Myers Squibb, Novartis, Amgen, Eli Lilly & Company, Vertex Pharmaceuticals, AstraZeneca, Celgene, Tesaro, Sanofi-Aventis, Biogen, Precision Health Economics, and Analysis Group. Sun acknowledges consulting fees unrelated to this work from Egalet, Inc., and the Mission LISA Foundation.
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).