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Credit: Kim Allison, MD, FCAP Updated CAP/ASCO guideline offers specific recommendations for handling and reporting breast cancer testing cases that indicate low estrogen receptor expression. Accurate endocrine receptor testing is critical to optimal treatment plans Newswise — Northfield, Ill. and Alexandria, Va.— The updated guideline for estrogen and progesterone receptor (ER/PgR) testing in breast cancer, published jointly today by the College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO), reaffirms much of the original guidance and has more specific recommendations for handling and reporting cases with low ER expression.  Globally, more than 1 million women are diagnosed annually with breast cancer, and receptor testing conducted on their biopsies typically shows that approximately eight in 10 of these women have ER-positive breast cancer. Well-performed tests are essential to identify those patients who could benefit from endocrine therapy. And more broadly, hormone receptor status can be valuable for tumor classification and other factors that inform treatment.  In a notable change, cases with 1-10% of cells staining for ER expression will now be reported as ER-low positive. Pathology reports for these cases should include a recommended comment that acknowledges the more limited data on endocrine responsiveness in this group. Also in such cases, pathologists should report the status of internal controls, with a special comment for specimens that lack internal positive controls. The new guideline also recommends that laboratories establish specific standard operating procedures to ensure the validity of ER-low positive (1-10%) or ER negative (0 or <1%) results and their interpretation.  Correlation of ER staining with the histologic features, and attention to other standard quality control measures, is also recommended, including additional steps to assess unusual or discordant results.    The utility of PgR testing continues to be largely prognostic in the ER-positive invasive cancer population, but testing using similar principles to ER testing is still recommended for invasive cancers.  The updated guideline also more clearly recommends that ER be tested in cases of newly diagnosed DCIS (without invasion) to help estimate potential benefit of endocrine therapy to reduce the risk of a future breast cancer event. But, specifically, PgR testing in DCIS is optional.  “Like the original guideline, invasive cancers with 1-100% ER staining are considered positive and eligible for endocrine therapy,” Kimberly Allison, MD, FCAP, pathologist and project co-chair explained. “But this update focuses on better assessment of cases with lower levels of ER expression. We wanted to establish guidance to help ensure that the results from hormone receptor testing in women diagnosed with breast cancer are as accurate as possible. This will give physicians and patients more information to guide them when making treatment decisions.”  “The critical point for clinicians is that they need to be aware of and able to discuss with patients the implications of ER-low positive test results,” explained Antonio Wolff, MD, FACP, FASCO, an oncologist representing ASCO and project co-chair. “We now have more standardized recommendations for these cases.”  Likewise, patients should be aware of their test results and should be encouraged to discuss decisions to use endocrine therapy with their clinical care team.  The update to this pivotal evidence-based guideline is available today in an early online release from the Archives of Pathology & Laboratory Medicine and Journal of Clinical Oncology.  In addition, CAP- and ASCO-developed resources to help clinicians implement the guideline are available at no charge via the society’s websites.

Newswise — SAN FRANCISCO, Calif. — Jan. 13, 2020 — A survey conducted by The Harris Poll has uncovered key gaps in American’s knowledge of eye health, and what they don’t know is putting them at risk of vision loss. With the number of people affected by potentially blinding eye diseases expected to double in the years ahead1, it’s critical that people better understand eye health. As the new year begins and people rededicate themselves to their health, the American Academy of Ophthalmology is urging Americans to get smart about eye health in 2020. This survey was conducted online by The Harris Poll on behalf of the American Academy of Ophthalmology in August 2019 among more than 3,500 U.S. adults age 18 and older. Here are some of the key findings: While 81% of adults say they are knowledgeable about eye/vision health, less than 1 in 5 (19%) were able to correctly identify the three main causes of blindness in the U.S., which are glaucoma, age-related macular degeneration (AMD) and diabetic eye disease. Less than half (47%) are aware that vision loss and blindness does not affect all people equally. Only around one-third of adults (37%) know you do not always experience symptoms before you lose vision to eye diseases. Less than half (47%) are aware your brain can make it difficult to know if you are losing your vision by adapting to vision loss. “Far too often, we witness the consequences of patients entering the ophthalmologist’s office too late to avoid severe vision loss,” said Anne L. Coleman, M.D., Ph.D., president of the American Academy of Ophthalmology. “In 2020, we want all Americans to have clear vision when it comes to eye health. That starts with educating yourself about eye diseases and visiting an ophthalmologist.” Ophthalmologists are medical and surgical physicians trained to recognize all the potential threats to vision, which is why the Academy recommends that healthy adults see an ophthalmologist for a comprehensive, baseline eye exam by age 40 and have their eyes checked every year or two at age 65 or older. The impacts of vision loss are also underappreciated. Another key finding showed that people are unaware that vision loss can also amplify the adverse effects of other chronic illnesses. Although the majority of adults (57%) are aware that vision loss in adults increases the risk for injury or death, only 1 in 4 (24%) know that vision loss in adults is associated with psychological problems such as social isolation and depression. Study after study has shown that people fear vision loss more than they fear cancer, stroke, heart disease and other serious health problems. What this new study shows is that Americans are scared about an issue they know very little about. The year 2020, with all its symbolism with clear vision, is the year to change that. For ophthalmologist-reviewed information about eye diseases and treatments, eye health news, and tools to locate an ophthalmologist, visit AAO.org/EyeSmart. EyeCare America® Can Help If you are concerned about the cost of the exam, the American Academy of Ophthalmology’s EyeCare America® program may be able to help. This national public service program provides eye care through volunteer ophthalmologists for eligible seniors 65 and older; and those at increased risk for eye disease. To see if you or your loved ones are eligible, visit www.aao.org/eyecareamerica.   About the Survey This survey was conducted online within the U.S. by The Harris Poll on behalf of the American Academy of Ophthalmology among 3,512 U.S. adults ages 18 and over between August 8 and 27, 2019. Data by race/ethnicity were weighted where necessary by gender, age, region, income, education, household size, marital status, employment, and specific eye conditions of interest to bring them into line with their actual proportions in the population. The data for each race/ethnicity group was then combined into a grand total to reflect the proportions of each race/ethnicity within the U.S. adult population. Propensity score weighting was also used to adjust for respondents’ propensity to be online. For additional details about the survey results, please contact Lindsey.Bailys@gcihealth.com.   About the American Academy of Ophthalmology The American Academy of Ophthalmology is the world’s largest association of eye physicians and surgeons. A global community of 32,000 medical doctors, we protect sight and empower lives by setting the standards for ophthalmic education and advocating for our patients and the public. We innovate to advance our profession and to ensure the delivery of the highest-quality eye care. Our EyeSmart® program provides the public with the most trusted information about eye health. For more information, visit aao.org.

Credit: Mark Cornelison | UK Photo University of Kentucky researchers (from left) Matthew Gentry, Haining Zhu and Lisha Kuang co-authored a study that shows a class of antibiotics could be a promising therapy for frontotemporal dementia. Newswise — LEXINGTON, Ky. (Jan. 10, 2020) — Researchers at the University of Kentucky’s College of Medicine have found that a class of antibiotics called aminoglycosides could be a promising treatment for frontotemporal dementia. Results of their proof of concept study, which was a collaborative effort between UK’s Department of Molecular and Cellular Biochemistry and the University of California San Francisco’s Department of Pathology, were recently published in the journal, Human Molecular Genetics. Frontotemporal dementia is the second-most common dementia after Alzheimer’s disease and the most common type of early onset dementia. It typically begins between ages 40 and 65 and affects the frontal and temporal lobes of the brain, which leads to behavior changes, difficulty speaking and writing, and memory deterioration. A subgroup of patients with frontotemporal dementia have a specific genetic mutation that prevents brain cells from making a protein called progranulin. Although progranulin is not widely understood, its absence is linked to the disease. A group led by Haining Zhu, a professor in UK’s Department of Molecular and Cellular Biochemistry, discovered that after aminoglycoside antibiotics were added to neuronal cells with this mutation, the cells started making the full-length progranulin protein by skipping the mutation. “These patients’ brain cells have a mutation that prevents progranulin from being made. The team found that by adding a small antibiotic molecule to the cells, they could ‘trick’ the cellular machinery into making it,” said Matthew Gentry, a co-author of the study and the Antonio S. Turco Endowed Professor in the Department of Molecular and Cellular Biochemistry. The researchers found two specific aminoglycoside antibiotics - Gentamicin and G418 - were both effective in fixing the mutation and making the functional progranulin protein. After adding Gentamicin or G418 molecules to the affected cells, the progranulin protein level was recovered up to about 50 to 60%. These results could be promising to drug development. Currently, there are no effective therapies for any type of dementia. After this preclinical proof of concept study, the next step is to study the antibiotics’ effects on mice with the mutation that causes frontotemporal dementia, Zhu says. Another focus is to possibly develop new compounds from Gentamicin and G418 that could be safer and more effective. Although Gentamicin is an FDA-approved medication, its clinical usage is limited as it is associated with a number of adverse side effects. “If we can get the right resources and physician to work with, we could potentially repurpose this drug. This is an early stage of the study, but it provides an important proof of concept that these aminoglycoside antibiotics or their derivatives can be a therapeutic avenue for frontotemporal dementia,” said Zhu. 

Credit: Alicia Ortega, MS   Newswise — For adult patients with brainstem high-grade gliomas — one of the rarest and deadliest forms of brain cancer — surgically removing the entire tumor may add many months or potentially years of survival beyond that offered by radiation and chemotherapy, according to results of a medical records study led by researchers at the Johns Hopkins Kimmel Cancer Center. The investigators point out that survival for these tumors has remained poor, with a median survival length of eight months after diagnosis in people who only receive a biopsy. However, if total surgical removal is an option for patients, the data in the records studied suggest it could boost this number to a median of 16 months or more.  “Knowing what these surgeries can do could help neurosurgeons, neuro-oncologists and patients have a better sense of what to expect so we can move forward toward better standardized care for these rare and critical tumors,” says study leader Debraj Mukherjee, M.D., M.P.H., assistant professor of neurosurgery at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center. The findings were reported online Oct. 16 in the Journal of Neuro-Oncology. Every year, about 10,000 patients in the U.S. are diagnosed with high-grade gliomas, aggressive cancers that arise from a brain cell type called glia, which form the “scaffolding” of the organ. Only a small fraction of these cancers form in the brainstem, a core structure critical for nearly all functions necessary for life, such as heart rate, breathing and consciousness.  Because of the vital nature of this region, brainstem high-grade gliomas have traditionally been treated only by chemotherapy and radiation. However, in recent years, Johns Hopkins and several other academic medical centers around the world have been able to safely access tumors through so-called “brainstem safe entry zones,” making surgery possible for previously inoperable tumors. Consequently, a growing number of patients have opted for partial or total removal of their tumors, according to the researchers. But because gliomas are rare, and the availability of surgical treatment relatively recent, it has been difficult to compare treatments, and unclear what kind of survival benefit surgery confers. To find out, Mukherjee, along with Johns Hopkins Kimmel Cancer Center postdoctoral fellow Adham M. Khalafallah, M.D., M.B.B.Ch., and their colleagues used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Result (SEER) database, an extensive collection of information on cancer patients gleaned from registries in 19 geographic regions that cover about 35% of the U.S. population. A search of this database, covering a time span from 1973 to 2015, turned up 103 patients with brainstem high-grade gliomas who underwent either a biopsy (15%) or some surgical intervention (85%) for their tumors. Of those who had surgery, about 19% underwent total surgical removal. Beyond information on interventions, SEER records included a wealth of other data on these patients, including age, race, marital status, size of their tumor, how far it had spread, if postoperative radiation treatment was done and length of survival after diagnosis. When the researchers analyzed this information, they found significantly longer survival in patients who had surgery. Compared with the median survival length of eight months after diagnosis in patients who had just a biopsy, those who had a partial resection survived about 11 months, and those who had a gross total resection survived about 16 months. In a fraction of patients who had other factors associated with longer survival, such as younger age and marital status, median survival with a total resection was up to four times higher than patients who only had biopsies. In the future, Mukherjee adds, it might be possible to boost survival even further by identifying biomarkers that could help personalize which treatments might benefit patients most. Other Johns Hopkins researchers who participated in this study include Joshua Doyle, Wuyang Yang, Yi Sun and Chetan Bettegowda.

Newswise — PHILADELPHIA – Cancer patients may one day be able to get their entire course of radiation therapy in less than a second rather than coming in for treatment over the course of several weeks, and researchers in the Abramson Cancer Center of the University of Pennsylvania have taken the first steps toward making it a reality. In a new report published today in the International Journal of Radiation Oncology, Biology, and Physics, researchers detail how they used proton radiation to generate the dosage needed to theoretically give a cancer patient their entire course of radiotherapy in one rapid treatment. It’s known as FLASH radiotherapy, and it’s an experimental paradigm that could represent a sea change for the world of oncology in the future. In this study, researchers also found FLASH demonstrated the same effect on tumors as traditional photon radiation while sparing healthy tissue due to the shorter exposure time. “This is the first time anyone has published findings that demonstrate the feasibility of using protons – rather than electrons – to generate FLASH doses, with an accelerator currently used for clinical treatments,” said the study’s co-senior author James M. Metz, MD, director of the Roberts Proton Therapy Center and chair of Radiation Oncology. The co-senior authors on the study are Constantinos Koumenis, PhD, the Richard H. Chamberlain Professor of Research Oncology, and Keith A. Cengel, MD, PhD, an associate professor of Radiation Oncology, both in Penn’s Perelman School of Medicine. Metz noted that other research teams have generated similar doses using electrons, which do not penetrate deep enough into the body to be clinically useful as a cancer treatment for internal tumors. Other groups have tried the approach with conventional photons, but currently available treatment devices do not have the ability to generate the necessary dosage.  This study shows, that with technical modifications, the currently available accelerators for protons can achieve FLASH doses with the biologic effects today.  The key for the Penn team was the ability to generate the dose with protons, and even in that setting, researchers had to specially develop the tools needed to effectively and accurately measure radiation doses, since the standard detectors were quickly saturated due to the high levels of radiation. The Roberts Proton Therapy Center includes a dedicated research room to run experiments like these, allowing investigators to use photon and proton radiation side-by-side just feet from the clinic. It’s one of the few facilities in the world with those unique features, and Metz said this infrastructure is what made Penn’s FLASH experiments possible. “We’ve been able to develop specialized systems in the research room to generate FLASH doses, demonstrate that we can control the proton beam, and perform a large number of experiments to help us understand the implications of FLASH radiation that we simply could not have done with a more traditional research setup,” Metz said. Researchers said they are already beginning to optimize how they would use this down the road for clinical trials, including taking the necessary steps to translate the ability from the research room to a clinical space, as well as designing a delivery system for FLASH in humans. The study’s co-lead authors are Eric S. Diffenderfer, Ioannis Verginadis, and Michele Kim. Additional Penn authors include Khayrullo Shoniyozov, Anastasia Velalopoulou, Denisa Goia, Mary Putt, Sarah Hagan, Stephen Avery, Kevin Teo, Wei Zou, Alexander Lin, Samuel Swisher-McClure, Cameron Koch, Ann R. Kennedy, Andy Minn, Amit Maity, Theresa M. Busch, and Lei Dong.

Credit: UTSW A re-analysis of clinical tests from three major U.S. laboratories showed whole exome sequencing routinely failed to adequately analyze large segments of DNA. UT Southwestern experts who conducted the review say the findings are indicative of a widespread issue for clinical laboratories. Highlights: Reanalysis of patient samples from 3 U.S. labs shows most tests didn’t adequately analyze more than a quarter of genes. Chance of detecting a disorder varied widely depending on which genes the lab completely analyzed in a given sample. Newswise — DALLAS – Jan. 6, 2020 – Children who undergo expansive genetic sequencing may not be getting the thorough DNA analysis their parents were expecting, say experts at UT Southwestern Medical Center. A review of clinical tests from three major U.S. laboratories shows whole exome sequencing routinely fails to adequately analyze large segments of DNA, a potentially critical deficiency that can prevent doctors from accurately diagnosing potential genetic disorders, from epilepsy to cancer. The reanalysis by UT Southwestern shows each lab on average adequately examined less than three-quarters of the genes – 34, 66, and 69 percent coverage – and had startlingly wide gaps in their ability to detect specific disorders. Researchers say they conducted the study because they believe vast differences in testing quality are endemic in clinical genetic sequencing but have not been well documented or shared with clinicians. “Many of the physicians who order these tests don’t know this is happening,” says Jason Park, M.D., Ph.D., associate professor of pathology at UT Southwestern. “Many of their patients are young kids with neurological disorders, and they want to get the most complete diagnostic test. But they don’t realize whole exome sequencing may miss something that a more targeted genetic test would find.” Whole exome sequencing, a technique for analyzing protein-producing genes, is increasingly used in health care to identify genetic mutations that cause disease – mostly in children but also in adults with rare or undiagnosed diseases. However, Park says the process of fully analyzing the approximately 18,000 genes in an exome is inherently difficult and prone to oversights. About half the tests do not pinpoint a mutation. The new study published in Clinical Chemistry gives insight into why some analyses may be coming back negative. Researchers re-analyzed 36 patients’ exome tests conducted between 2012 and 2016 – 12 from each of the three national clinical laboratories – and found starkly contrasting results and inconsistency with which genes were completely analyzed. A gene was not considered completely analyzed unless the lab met an industry-accepted threshold for adequate analysis of all DNA that encodes protein, which is defined as sequencing that segment at least 20 times per test. Notably, less than 1.5 percent of the genes were completely analyzed in all 36 samples. A review of one lab’s tests showed 28 percent of the genes were never adequately examined and only 5 percent were always covered. Another lab consistently covered 27 percent of the genes. “And things really start to fall apart when you start thinking about using these tests to rule out a disease,” Park says. “A negative exome result is meaningless when so many of the genes are not thoroughly analyzed.” For example, the chances of detecting an epileptic disorder from any of the 36 tests varied widely depending on which genes were analyzed. One lab conducted several patient tests that fully examined more than three quarters of the genes associated with epilepsy, but the same lab had three other patient samples in which less than 40 percent were completely analyzed. Three tests from another lab came in at under 20 percent.  “When we saw this data we made it a regular practice to ask the labs about coverage of specific genes,” says Garrett Gotway, M.D., Ph.D., a clinical geneticist at UT Southwestern who is the corresponding author of the study. “I don’t think you can expect complete coverage of 18,000 genes every time, but it’s fair to expect 90 percent or more.” The findings build upon previous research that showed similar gaps and disparities in whole genome sequencing, a technique that examines all types of genes, regardless of whether they produce proteins. Gotway says he hopes the findings will prompt more physicians to ask labs about which genes were covered and push for improved consistency in testing quality. He also encourages physicians – even before ordering the test – to consider whether whole exome sequencing is the best approach for the patient. “Clinical exomes can be helpful in complex cases, but you probably don’t need one if a kid has epilepsy and doesn’t have other complicating clinical problems,” Gotway says. “There’s a decent chance the exome test will come back negative and the parents are still left wondering about the genetic basis for their child’s disease.” In those cases, Gotway suggests ordering a smaller genetic test that completely analyzes a panel of genes associated with that disease. He says they’re less expensive and just as likely to help physicians find answers. About the study Park is medical director of the Advanced Diagnostics Laboratory at Children’s Medical Center Dallas. Gotway is assistant professor of pediatrics and internal medicine. Both are members of UT Southwestern’s Eugene McDermott Center for Human Growth and Development. About UT Southwestern Medical Center UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

Newswise — Nurses with specialty certification may play an integral part in speeding translation of the latest research into everyday clinical practice, thereby ensuring that critically ill patients receive the highest quality of care, according to a study conducted at UPMC (University of Pittsburgh Medical Center). A survey of 268 critical care nurses in six UPMC hospitals found a strong association between nurses who were certified in critical care and their knowledge of and perceived value in specific evidence-based practices used to care for patients receiving mechanical ventilation. The results, “Factors Associated with Nurses’ Knowledge of and Perceived Value in Evidence-Based Practices,” are published in the January issue of American Journal of Critical Care (AJCC). Overall, respondents reported a high level of perceived knowledge of three specific evidence-based practices used in caring for patients receiving mechanical ventilation: spontaneous breathing trials, lung-protective ventilation and daily interruption of sedation. When compared with noncertified nurses, certified nurses reported greater perceived value of all three practices and significantly more perceived knowledge of spontaneous breathing trials and lung-protective ventilation. In addition, all respondents reported strong professional identity, self-efficacy and role clarity, all with mean scores greater than 4.0 on a 5-point scale. Nurses who held specialty certification reported higher levels of self-efficacy and role clarity than their noncertified colleagues. An interdisciplinary research team with the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center at the University of Pittsburgh’s Department of Critical Care Medicine conducted the study in 12 adult intensive care units (ICUs) within six UPMC hospitals. The 44-item survey was associated with a larger study examining ICU team function and the delivery of evidence-based practices, with funding from the U.S. National Institutes of Health and its National Heart, Lung, and Blood Institute. “Many evidence-based practices remain underused, partly because of gaps between providers’ attitudes toward practices and the delivery of care at the bedside. Our findings support the value of nurses with specialty certification, especially among institutions that aim to improve outcomes and increase the adoption of evidence-based practices,” said co-author Kristin Hittle Gigli, PhD, RN, CPNP-AC, CCRN, a postdoctoral research fellow at the CRISMA Center.    The results did not indicate a strong relationship between nurses’ education levels and evidence-based practices, and the researchers point to the high percentage of respondents with a bachelor’s degree or higher (70.9%) as a potential factor in the lack of association. In addition, the survey did not ask about years of experience or certifications other than CCRN, which may be additional elements influencing nurses’ individual beliefs and perceptions. CCRN® specialty certification is for nurses who provide direct care to acutely/critically ill adult, pediatric or neonatal patients regardless of their physical location. Nurses interested in this certification may work in areas such as intensive care units, cardiac care units, combined ICU/CCUs, medical/surgical ICUs, trauma units or critical care transport/flight. CCRN is one of several credentials granted by AACN Certification Corporation, the credentialing arm of the American Association of Critical-Care Nurses. Currently, more than 120,000 acute and critical care nurses hold AACN Certification Corporation credentials: CCRN, CCRN-K, CCRN-E, PCCN, PCCN-K, ACNPC, ACNPC-AG, CCNS, ACCNS-AG, ACCNS-P, ACCNS-N, CMC and CSC. For more information, visit https://www.aacn.org/certification. To access the article and full-text PDF, visit the AJCC website at www.ajcconline.org.

A rendering of amyloid protein plaques accumulating between neurons in the brain. Credit: National Institute of Aging   Newswise — Writing in the December 30, 2019 online issue of Neurology, researchers at University of California San Diego School of Medicine and Veterans Affairs San Diego Healthcare System report that accumulating amyloid — an abnormal protein linked to neurodegenerative conditions such as Alzheimer’s disease (AD) — occurred faster among persons deemed to have “objectively-defined subtle cognitive difficulties” (Obj-SCD) than among persons considered to be “cognitively normal.” Classification of Obj-SCD, which has been previously shown to predict progression to mild cognitive impairment (MCI) and dementia, is determined using non-invasive but sensitive neuropsychological measures, including measures of how efficiently someone learns and retains new information or makes certain types of errors. The new findings, say authors, suggest that Obj-SCD can be detected during the preclinical state of AD when amyloid plaques are accumulating in the brain, neurodegeneration is just starting, but symptoms of impairment on total scores on thinking and memory tests have not yet been recorded. “The scientific community has long thought that amyloid drives the neurodegeneration and cognitive impairment associated with Alzheimer’s disease,” said senior author Mark W. Bondi, PhD, professor of psychiatry at UC San Diego School of Medicine and the VA San Diego Healthcare System. “These findings, in addition to other work in our lab, suggest that this is likely not the case for everyone and that sensitive neuropsychological measurement strategies capture subtle cognitive changes much earlier in the disease process than previously thought possible. “This work, led by Dr. Kelsey Thomas, has important implications for research on treatment targets for AD, as it suggests that cognitive changes may be occurring before significant levels of amyloid have accumulated. It seems like we may need to focus on treatment targets of pathologies other than amyloid, such as tau, that are more highly associated with the thinking and memory difficulties that impact people’s lives.” Study participants were enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), an on-going effort (launched in 2003) to test whether regular, repeated brain imaging, combined with other biological markers and clinical assessments, can measure the progression of MCI and early AD.  Seven hundred and forty-seven persons were involved in this study: 305 deemed cognitively normal, 153 with Obj-SCD and 289 MCI. All underwent neuropsychological testing and both PET and MRI scans. The research team found that amyloid accumulation was faster in persons classified with Obj-SCD than in the cognitively normal group. Those classified as Obj-SCD also experienced selective thinning of the entorhinal cortex, a region of the brain impacted very early in Alzheimer’s disease and associated with memory, navigation and perception of time. Persons with MCI had more amyloid in their brain at the start of the study, but they did not have faster accumulation of amyloid compared to those with normal cognition. However, those with MCI had more widespread temporal lobe atrophy, including the hippocampus. Broadly speaking, scientists believe that for most people, AD is likely caused by a combination of genetic, lifestyle and environmental factors. Increasing age is a primary, known risk factor. The amyloid hypothesis or amyloid cascade model posits that accumulating amyloid protein plaques in the brain kill neurons and gradually impair specific cognitive functions, such as memory, resulting in AD dementia. However, many scientists are now questioning the amyloid hypothesis given the large number of clinical trials in which drugs targeted and successfully cleared amyloid from the brain but did not impact the trajectory of cognitive decline. The ability to identify those at risk for AD before significant impairment and before or during the phase of faster amyloid accumulation would be a clinical boon, said authors, providing both a way to monitor disease progression and a window of opportunity to apply potential preventive or treatment strategies. Currently, both approaches are limited. Some risk factors for Alzheimer’s can be minimized, such as not smoking, managing vascular risk factors such as hypertension or following a healthy diet with regular exercise. There are a handful of medications approved for treating symptoms of AD, but as yet, there is no cure. “While the emergence of biomarkers of Alzheimer’s disease has revolutionized research and our understanding of how the disease progresses, many of these biomarkers continue to be highly expensive, inaccessible for clinical use or not available to those with certain medical conditions,” said first author Thomas, PhD, assistant professor of psychiatry at UC San Diego School of Medicine and research health scientist at the VA San Diego Healthcare System. “A method of identifying individuals at risk for progression to AD using neuropsychological measures has the potential to improve early detection in those who may otherwise not be eligible for more expensive or invasive screening.” Co-authors of this study include Kelsey R. Thomas, Katherine J. Bangen, Emily C. Edmonds, Christina G. Wong, Shanna Cooper, Lisa Delano-Wood, UC San Diego and VA San Diego Healthcare System; and Alexandra J. Weigand, UC San Diego, VA San Diego Healthcare System and San Diego State University/UC San Diego Joint Doctoral Program in Clinical Psychology. Funding for this study came, in part, from the National Institutes of Health (grants R01 AG049810, K24 AG026431), the Alzheimer’s Association (AARF-17-528918), the U.S. Department of Veterans Affairs Clinical Sciences Research and Development Service (1IK2CX001865), and the Alzheimer’s Disease Neuroimaging Initiative, which is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Disclosure: Mark Bondi receives royalties from Oxford University Press and serves as a consultant for Eisai, Novartis and Roche pharmaceutical companies. Full study: https://n.neurology.org/content/early/2019/12/29/WNL.0000000000008838

Surface of a multicillated cell        Credit: Andrew Holland Newswise — One of the wonders of cell biology is its symmetry. Mammalian cells have one nucleus and one cell membrane, and most humans have 23 pairs of chromosomes. Trillions of mammalian cells achieve this uniformity — but some consistently break this mold to fulfill unique functions. Now, a team of Johns Hopkins Medicine researchers have found how these outliers take shape. In experiments with genetically engineered mice, a research team has ruled out a mechanism that scientists have long believed controls the number of hairlike structures, called cilia, protruding on the outside of each mammalian cell. They concluded that control of the cilia count might rely instead on a process more commonly seen in non-mammalian species. The experiments, described Dec. 2 in Nature Cell Biology and led by Andrew Holland, Ph.D., associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine, may eventually help scientists learn more about human diseases related to cilia function, such as respiratory infections, infertility and hydrocephaly. Cilia are ancient structures that first appeared on single-celled organisms as small hairlike “fingers” that act as motors to move the cell or antennae to sense the environment. Nearly all human cells have at least one cilium that senses physical or chemical cues. However, some specialized cell types in humans, such as those lining the respiratory and reproductive tracts, have hundreds of cilia on their surface that beat in waves to move fluids through the system. “Our main question was how these multicilliated cells become so dramatically different than the rest of the cells in our body,” says Holland. “Most cells make exactly one cilium per cell, but these highly specialized cells give up on this tight numerical control and make hundreds of cilia.” In an effort to answer the question, Holland and his team took a closer look at the base of cilia, the place where the organelles attach and grow from the surface of the cell. This base is a microscopic, cylinder-shaped structure called a centriole. In single-ciliated cells, Holland says, centrioles are created before a cell divides. A cell contains two-parent centrioles that each duplicate so that both new cells gets one pair of centrioles — the oldest of these two centrioles then goes on to form the base of the cilium. However, multicilliated cells create unique structures, called deuterosomes, that act as a copy machine to enable the production of tens to hundreds of centrioles, allowing these cells to create many cilia. “Deuterosomes are only present in multicilliated cells, and scientists have long thought they are central for determining how many centrioles and cilia are formed,” says Holland. To test this, Holland and his team developed a mouse model that lacked the gene that creates deuterosomes. Then, they analyzed the tissues that carry multicilliated cells and counted their cilia. The researchers were surprised to find that the genetically engineered mice had the same number of cilia on cells as the mice with deuterosomes, ruling out the central role of deuterosomes in controlling the number of cilia. For example, the multicilliated cells lining the trachea all had 200–300 cillia per cell. The researchers also found that cells without deuterosomes could make new centrioles just as quickly as cells with them. With this surprising result in hand, the researchers engineered mouse cells that lacked both deuterosomes and parent centrioles, and then counted the number of cilia formed in multicilliated cells. “We figured that with no parent centrioles and no deuterosomes, the multicilliated cells would be unable to create the proper number of new cilia,” says Holland. Remarkably, Holland says, even the lack of parent centrioles had no effect on the final cilia number. Most cells in both normal and genetically engineered groups created between 50 and 90 cilia. “This finding changes the dogma of what we believed to be the driving force behind centriole assembly,” explains Holland. “Instead of needing a platform to grow on, centrioles can be created spontaneously.” While uncommon in mammals, the so-called de novo generation of centrioles is not new to the animal kingdom. Some species, such as the small flatworm planaria, lack parent centrioles entirely, and rely on de novo centriole generation to create the cilia they use to move. In further experiments on genetically engineered mice, Holland found that all the spontaneously created centrioles were assembled within a region of the cell rich with fibrogranular material — the protein components necessary to build a centriole. He says he suspects that proteins found in that little-understood area of the cell contain the essential elements necessary to construct centrioles and ultimately control the number of cilia that are formed. Everything else, the deuterosomes and even the parent centrioles, are “not strictly necessary,” he says. “We think that the deuterosomes function to relieve pressure on the parent centrioles from the demands of making many new centrioles, freeing up parent centrioles to fulfill other functions,” says Holland. A better understanding of mechanisms that limit cilia number in human cells could potentially advance efforts to treat cilia-related disorders, he said, by identifying targets for drugs. Other researchers involved in this study include Olivier Mercey of the Paris Sciences et Lettres Research University; Michelle Levine, Gina LoMastro, Valerie Gomez and Abhijay Kumar of the Johns Hopkins University School of Medicine; Philippe Rostaing, Nathalie Spassky and Alice Meunier of the Paris Sciences et Lettres Research University, the French National Centre for Scientific Research and INSERM; and Brian Mitchell of Northwestern University. This work was supported by the National Institute of General Medical Sciences (R01GM114119, R01GM133897, R01GM089970), the American Cancer Society (RSG-16-156-01-CCG), the Agence Nationale de la Recherche Investissements d’Avenir (ANR-10-LABX-54 MEMO LIFE, ANR-11-IDEX-0001-02 PSL), the European Research Council (647466) and the French National Research Agency (ANRJC JC-15-CE13-0005-01. The authors declare no competing interests.

Newswise — BLOOMINGTON, Ind. -- Indiana University researchers have discovered that a chemical compound found in essential oils improves the healing process in mice when it is topically applied to a skin wound -- a finding that could lead to improved treatments for skin injuries in humans. IU scientists also reported that skin tissue treated with the chemical compound, beta-carophyllene -- which is found in lavender, rosemary and ylang ylang, as well as various herbs and spices such as black pepper -- showed increased cell growth and cell migration critical to wound healing. They also observed increased gene expression of hair follicle stem cells in the treated tissue. The scientists did not find any involvement of the olfactory system in the wound healing. Their research was published Dec. 16 in the journal PLOS ONE. "This is the first finding at the chemical-compound level showing improved wound healing in addition to changes in gene expression in the skin," said Sachiko Koyama, corresponding author on the paper, who, at the time of this research, was an associate scientist at the IU School of Medicine and is currently a visiting scientist in the IU College of Arts and Sciences' Department of Biology. "The way gene expression changed also suggests not only improved wound healing but also the possibility of less scar formation and a more full recovery. "It's an example that essential oils work; however, it's not through our sense of smell." Essential oils are natural, concentrated oils extracted from plants. Their use by humans dates back to ancient Egypt, but the scented oils have experienced a resurgence in popularity in the U.S. over the past few years, with many people using them for aromatherapy. Koyama, whose original field of study is pheromones, said she wasn't interested in essential oils at first. The project started when she saw several students studying the wound healing process in mice in the Medical Sciences Program at the IU School of Medicine-Bloomington. Having previously worked in the IU College of Arts and Sciences' Department of Psychological and Brain Sciences, where scientists are working with cannabinoid receptors, Koyama knew that beta-caryophyllene activates not only olfactory receptors but also cannabinoid receptor 2 (CB2), which has anti-inflammatory impact when it is activated. "In the wound healing process, there are several stages, starting from the inflammatory phase, followed by the cell proliferation stage and the remodeling stage," she said. "I thought maybe wound healing would be accelerated if inflammation was suppressed, stimulating an earlier switch from the inflammatory stage to the next stage." This accelerated the wound healing process, she said, but the resulting change in gene expression indicates that the improved healing is not merely achieved through activation of the CB2 receptor. "It's possibly more complicated," Koyama said. "Our findings suggest the involvements of some other routes in addition to CB2. I hope to clarify the mechanisms of action in the near future." Although the study's results are promising, Koyama said she wouldn't recommend that people start treating their injuries with just any essential oils, as her research applies to a very specific chemical compound with known purity, diluted in a specific concentration. "It's not very precise to use the essential oils themselves because there are differences," she said. "Even if you say you used lavender, when the lavender was harvested, where it was harvested, how it was stored -- all of this makes a difference in the chemical composition." Koyama said further research is required to figure out how beta-carophyllene might be used to develop new treatments for skin wounds in humans. She said she hopes to better understand the mechanisms that accelerate the healing process and to find a combination of chemical compounds that could be used together to accelerate drug delivery and chemical stability, which is important for avoiding or suppressing allergic responses caused by oxidation of the chemical compounds. "We still need thorough scientific studies at the chemical-compound level and also to test the combinations of these chemical compounds," Koyama said. "For example, there are studies showing that linalool -- another compound found in lavender -- can suppress anxiety through the olfactory system. There could be the best combinations of chemical compounds at specific ratios, and we might be able to do prescriptions of aroma chemical compounds, depending on the specific treatment goals. "There are many things to test before we can start using it clinically, but our results are very promising and exciting; someday in the near future, we may be able to develop a drug and drug delivery methods using the chemical compounds found in essential oils." Additional IU authors on the paper include Anna Purk and Anthony Mescher of the IU School of Medicine; and, in the IU College of Arts and Sciences, Manpreet Kaur of the Department of Psychological and Brain Sciences, Helena A. Soini and Milos V. Novotny of the Department of Chemistry and the Institute for Pheromone Research, Keith Davis of the Department of Biology, and C. Cheng Kao of the Department of Molecular and Cellular Biochemistry. Hiroaki Matsunami of Duke University also authored the paper. This research was supported by the Office of the Vice Provost of Research at IU Bloomington through a Collaborative Research and Creative Activity Funding Award to Koyama. Purk and Kaur worked on the study as awardees of the Research Experience for Undergraduate Women scholarship from the IU Center of Excellence for Women in Technology. IU Research Indiana University's world-class researchers have driven innovation and creative initiatives that matter for nearly 200 years. From curing testicular cancer to collaborating with NASA to search for life on Mars, IU has earned its reputation as a world-class research institution. Supported by $680 million last year from our partners, IU researchers are building collaborations and uncovering new solutions that improve lives in Indiana and around the globe.