ewswise — Rockville, Md. – Data being presented at the 2021 virtual meeting of the Association for Research in Vision and Ophthalmology (ARVO) highlights the significant impact of inherited retinal diseases (IRD) in the United States and Canada. Continuing their 2019 cost-of-illness of IRD studies in the Republic of Ireland and the United Kingdom (IRD Counts), Retina International sought to expand on the limited data illustrating the impact of IRDs from a socio-economic perspective. Given their larger population, data from the U.S. and Canada was a natural next step. In addition to the familial burden exposed in the study, the team noted that current assessment models of therapies do not appropriately reflect how little people living with IRD interact with health systems compared to the total cost burden of living with an IRD. “People living with an IRD interact with health systems at a very low level compared to the total cost burden of living with an IRD. The Cost of Illness study in the United States and Canada clearly demonstrates that current assessment models for reimbursement of therapies do not appropriately reflect this and therefore need urgent review,” says Avril Daly of Retina International. Notable results included: Productivity losses were the second highest burden in both the U.S. and Canada, amounting to US$4.056 billion, and CAN$205.1 million Persons with an IRD in the U.S. and Canada were 28.8% and 24.4% less likely to be in paid employment than the general population In the U.S. and Canada IRDs resulted in a 0.3% and 1.4% reduction in productivity while at work, respectively. The health systems cost in both regions was low at US$2.216 billion and CAN$37.8 million, respectively. Retina International and its partners developed the North American-based study, “to be utilized and referred to by populations across the globe to support access to services and care pathways, access to clinical trials and treatments. Most importantly, it highlights the need for continued research into IRDs to understand disease pathways and to find treatments and cures,” says Daly.
Newswise — As the COVID-19 pandemic has progressed, it has become clear that many survivors — even those who had mild cases — continue to manage a variety of health problems long after the initial infection should have resolved. In what is believed to be the largest comprehensive study of long COVID-19 to date, researchers at Washington University School of Medicine in St. Louis showed that COVID-19 survivors — including those not sick enough to be hospitalized — have an increased risk of death in the six months following diagnosis with the virus. The researchers also have catalogued the numerous diseases associated with COVID-19, providing a big-picture overview of the long-term complications of COVID-19 and revealing the massive burden this disease is likely to place on the world’s population in the coming years. The study, involving more than 87,000 COVID-19 patients and nearly 5 million control patients in a federal database, appears online April 22 in the journal Nature. “Our study demonstrates that up to six months after diagnosis, the risk of death following even a mild case of COVID-19 is not trivial and increases with disease severity,” said senior author Ziyad Al-Aly, MD, an assistant professor of medicine. “It is not an exaggeration to say that long COVID-19 — the long-term health consequences of COVID-19 — is America’s next big health crisis. Given that more than 30 million Americans have been infected with this virus, and given that the burden of long COVID-19 is substantial, the lingering effects of this disease will reverberate for many years and even decades. Physicians must be vigilant in evaluating people who have had COVID-19. These patients will need integrated, multidisciplinary care.” In the new study, the researchers were able to calculate the potential scale of the problems first glimpsed from anecdotal accounts and smaller studies that hinted at the wide-ranging side effects of surviving COVID-19, from breathing problems and irregular heart rhythms to mental health issues and hair loss. “This study differs from others that have looked at long COVID-19 because, rather than focusing on just the neurologic or cardiovascular complications, for example, we took a broad view and used the vast databases of the Veterans Health Administration (VHA) to comprehensively catalog all diseases that may be attributable to COVID-19,” said Al-Aly, also director of the Clinical Epidemiology Center and chief of the Research and Education Service at the Veterans Affairs St. Louis Health Care System. The investigators showed that, after surviving the initial infection (beyond the first 30 days of illness), COVID-19 survivors had an almost 60% increased risk of death over the following six months compared with the general population. At the six-month mark, excess deaths among all COVID-19 survivors were estimated at eight people per 1,000 patients. Among patients who were ill enough to be hospitalized with COVID-19 and who survived beyond the first 30 days of illness, there were 29 excess deaths per 1,000 patients over the following six months. “These later deaths due to long-term complications of the infection are not necessarily recorded as deaths due to COVID-19,” Al-Aly said. “As far as total pandemic death toll, these numbers suggest that the deaths we’re counting due to the immediate viral infection are only the tip of the iceberg.” The researchers analyzed data from the national health-care databases of the U.S. Department of Veterans Affairs. The dataset included 73,435 VHA patients with confirmed COVID-19 but who were not hospitalized and, for comparison, almost 5 million VHA patients who did not have a COVID-19 diagnosis and were not hospitalized during this time frame. The veterans in the study were primarily men (almost 88%), but the large sample size meant that the study still included 8,880 women with confirmed cases. To help understand the long-term effects of more severe COVID-19, the researchers harnessed VHA data to conduct a separate analysis of 13,654 patients hospitalized with COVID-19 compared with 13,997 patients hospitalized with seasonal flu. All patients survived at least 30 days after hospital admission, and the analysis included six months of follow-up data. The researchers confirmed that, despite being initially a respiratory virus, long COVID-19 can affect nearly every organ system in the body. Evaluating 379 diagnoses of diseases possibly related to COVID-19, 380 classes of medications prescribed and 62 laboratory tests administered, the researchers identified newly diagnosed major health issues that persisted in COVID-19 patients over at least six months and that affected nearly every organ and regulatory system in the body, including: Respiratory system: persistent cough, shortness of breath and low oxygen levels in the blood. Nervous system: stroke, headaches, memory problems and problems with senses of taste and smell. Mental health: anxiety, depression, sleep problems and substance abuse. Metabolism: new onset of diabetes, obesity and high cholesterol. Cardiovascular system: acute coronary disease, heart failure, heart palpitations and irregular heart rhythms. Gastrointestinal system: constipation, diarrhea and acid reflux. Kidney: acute kidney injury and chronic kidney disease that can, in severe cases, require dialysis. Coagulation regulation: blood clots in the legs and lungs. Skin: rash and hair loss. Musculoskeletal system: joint pain and muscle weakness. General health: malaise, fatigue and anemia. While no survivor suffered from all of these problems, many developed a cluster of several issues that have a significant impact on health and quality of life. Among hospitalized patients, those who had COVID-19 fared considerably worse than those who had influenza, according to the analysis. COVID-19 survivors had a 50% increased risk of death compared with flu survivors, with about 29 excess deaths per 1,000 patients at six months. Survivors of COVID-19 also had a substantially higher risk of long-term medical problems. “Compared with flu, COVID-19 showed remarkably higher burden of disease, both in the magnitude of risk and the breadth of organ system involvement,” Al-Aly said. “Long COVID-19 is more than a typical postviral syndrome. The size of the risk of disease and death and the extent of organ system involvement is far higher than what we see with other respiratory viruses, such as influenza.” In addition, the researchers found that the health risks from surviving COVID-19 increased with the severity of disease, with hospitalized patients who required intensive care being at highest risk of long COVID-19 complications and death. “Some of these problems may improve with time — for example, shortness of breath and cough may get better — and some problems may get worse,” Al-Aly added. “We will continue following these patients to help us understand the ongoing impacts of the virus beyond the first six months after infection. We’re only a little over a year into this pandemic, so there may be consequences of long COVID-19 that are not yet visible.” In future analyses of these same datasets, Al-Aly and his colleagues also plan to look at whether patients fared differently based on age, race and gender to gain a deeper understanding of the risk of death in people with long COVID-19. Photo Credit: Sara Moser A new study from Washington University School of Medicine in St. Louis shows that even mild cases of COVID-19 increase the risk of death in the six months following diagnosis and that this risk increases with disease severity. The comprehensive study also catalogues the wide-ranging and long-term health problems often triggered by the infection, even among those not hospitalized.
American Association for Cancer Research meeting is premier venue for presenting cancer research results Newswise — Atlantic Health System Cancer Care physicians are co-authors of five original studies presented at this year’s AACR Annual Meeting, held virtually April 10-15 and May 17-21. The AACR meeting is one of the world’s premier scientific gatherings of cancer specialists and researchers. “Atlantic Health System Cancer Care is extremely proud of its role, helping to lead these studies alongside some of the world’s best-known cancer researchers,” said Eric Whitman, MD, medical director, Atlantic Health System Cancer Care and director of the Atlantic Melanoma Center. “Our physicians conduct the most innovative research and provide world-class care seldom found outside of major academic medical centers. These innovative clinical trials offer more treatment options for patients, both in our area and in some cases, around the world.” Studies presented at the AACR meeting were co-authored by Dr. Whitman; Missak Haigentz, MD, chair of hematology/oncology at Morristown Medical Center, medical director of hematology/oncology for Atlantic Health System and principal investigator, Atlantic Health Cancer Consortium NCORP; and Angela Alistar, MD, medical director of GI medical oncology and the Breakthrough Treatment Center at Morristown Medical Center. See below for links to the study abstracts, which are now live, and brief descriptions of the studies: CT008 - Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up Dr. Whitman; presentation Dr. Whitman and colleagues presented 28-month follow-up data on the ongoing global phase 2, multicenter clinical trial of a new type of investigational cancer treatment known as lifileucel (LN-144) for advanced (Stage IV) melanoma. Lifileucel is a TIL (tumor infiltrating lymphocyte) therapy, in which the patient’s own immune system cells are removed from his/her tumor, treated with an immune booster and then infused back into the patient, along with a medication that stimulates the immune system. All participants in the study have metastatic melanoma that has progressed despite prior treatment with other therapies, including anti-PD-1 (checkpoint inhibitor) immunotherapy and BRAF/MEK inhibitor targeted therapy. At 28 months, lifileucel therapy has shown an overall response rate (ORR) of 36.4%. The study, which is ongoing, is sponsored by Iovance Biotherapeutics. Dr. Whitman and co-investigators presented earlier results at ASCO 2020. (NCT02360579CT201) Early report of a phase I/II study of human placental hematopoietic stem cell derived natural killer cells (CYNK-001) for the treatment of adults with COVID-19 (NCT04365101) Dr. Whitman; e-poster Dr. Whitman and colleagues published interim phase 1 results from the first study to evaluate the safety and efficacy of CYNK-001 (Celularity, Inc.) to treat patients with SARS-CoV-2 (the virus that causes COVID-19). The investigational drug was previously only tested against various types of cancer. CYNK-001 is the only cryopreserved, allogeneic, off-the-shelf, natural killer (NK) cell therapy being developed from placental hematopoietic stem cells as a potential treatment option for various blood cancers, solid tumors, and infectious disease. NK cells are a unique class of immune cells, innately capable of targeting cancer cells and interacting with adaptive immunity (specialized immunity to certain disease causing agents). CYNK-001 has been shown to be toxic to various types of cancer cells and secretes immune-modulating cell-signaling proteins (cytokines) when they reach their target. Patients with moderate to severe COVID-19 not requiring intensive care or mechanical ventilation were enrolled in this study. Infusions of CYNK-001 were generally well tolerated, and three of four patients showed improvement in oxygenation, lung inflammation and medical imaging findings. Phase 1 is still ongoing. Once it is complete, a randomized, phase 2 clinical trial will test the efficacy of this therapy for SARS-CoV-2 against the best available therapy. 1671 - Evaluation of total PD-1 expression using multi-color flow cytometry in metastatic non-small Cell lung cancer patients treated with multi-neoantigen vector (ADXS-503) alone and in combination of pembrolizumab to assess T-cell & T-cell memory subset Dr. Haigentz; e-poster Dr. Haigentz and colleagues tested novel laboratory assays developed by Precision for Medicine to be used as biomarkers in Advaxis clinical trials of ADXS-503 alone and in combination with pembrolizumab (Keytruda) for metastatic non-small cell lung cancer. ADXS-503 is a new type of investigational cancer drug that targets “hotspot” mutations that commonly occur in specific cancer types. Pembrolizumab is an immunotherapy that targets the PD-1 pathway, which protects cancer cells from immune attack. It is commonly used to treat this type of lung cancer. The researchers used the lab assays to examine frozen blood cells from individuals treated with the two-drug combination and those treated with ADXS-503 alone, in order to detect freestanding PD-1 proteins and PD-1 proteins bound to pembrolizumab. The assays were effective at detecting PD-1 on various immune T cells. Dr. Haigentz and colleagues state that the assays will help in the evaluation of total PD-1 expression in T cells when PD-1 blocking immunotherapies are used. These results may also support the combination of ADXS-503 with PD-1 focused therapies that could lead to more effective cancer immunotherapies. CT174 - Phase II study of avelumab and trastuzumab with FOLFOX chemotherapy in previously untreated HER2-amplified metastatic gastroesophageal adenocarcinoma Dr. Alistar; e-poster In a phase 2 study, Dr. Alistar and colleagues tested a combination of avelumab, trastuzumab and FOLFOX with patients with previously untreated metastatic gastric and gastric cancer that overexpresses the HER2 gene. Avelumab (Bavencio) is a monoclonal antibody immunotherapy known as an anti-PD-L1 therapy or immune checkpoint inhibitor, while trastuzumab (Herceptin) is also a monoclonal antibody that targets HER2 receptors. FOLFOX is a standard combination of chemotherapeutic drugs. The researchers added avelumab to the standard trastuzumab and FOLFOX regimen for these types of cancer. Study investigators showed that this combination therapy generated anti-tumor activity and compared favorably to previous studies of trastuzumab and chemotherapy. Dr. Alistar and colleagues are excited about the potential for adding checkpoint inhibitors to the chemotherapy/trastuzumab combination for these types of advanced gastrointestinal cancers. Some patients in the study were still being treated at the time the research abstract was submitted to the AACR. Additional lab-based studies are now underway. Atlantic Health System Cancer Care is the only cancer program in New Jersey involved in this study. (NCT03783936) CT177 - A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC) Dr. Alistar; e-poster To date, physicians have been unable to improve the health of people with metastatic pancreatic adenocarcinoma, the most common type of pancreatic cancer, with checkpoint inhibitor immunotherapy. Preclinical research has shown that the inhibition of the CXCR4 protein helps makes cancer cells more accessible to checkpoint inhibitors. In the second cohort of phase 2a COMBAT clinical trial, Dr. Alistar and colleagues tested BioLineRx Ltd.’s CXCR4 inhibitor BL-8040 in combination with checkpoint inhibitor pembrolizumab (Keytruda) and a type of chemotherapy against this Stage IV cancer. The study had encouraging results, with a confirmed objective response rate of 13.2%, 5.6 month median duration of benefit from the treatment, overall survival average of 6.5 months and progression free survival of four months. The investigators concluded that the therapeutic combination should be tested against this late-stage cancer in a randomized clinical trial. (NCT02826486) For information on current Atlantic Health System Cancer Care clinical trials, go to: www.atlantichealth.org/research. To learn more about the 2021 AACR Annual Meeting, go to: https://www.aacr.org/meeting/aacr-annual-meeting-2021/.
A new state-by-state analysis shows a statistical association between high adherence to mask wearing and reduced rates of COVID-19 in the U.S. Charlie Fischer and colleagues at the Boston University School of Public Health in Massachusetts present these findings in the open-access journal PLOS ONE on [DATE]. During the COVID-19 pandemic, different states have enacted different policies on mask wearing, with some states having no mask requirements and others requiring masks in all public spaces. Understanding the link between mask wearing and COVID-19 rates could help inform policies to mitigate stress on healthcare systems, economic instability, and death. To help clarify the effects of mask wearing, Fischer and colleagues examined publicly available data on mask-wearing policies, people’s self-reported habits on mask wearing in public, and COVID-19 rates for all 50 U.S. states and Washington, D.C. They accounted for a one-month delay between mask wearing and its subsequent potential impact on COVID-19 rates from May through October 2020. For this analysis, they considered rates of more than 200 cases per 100,000 residents to be high. The analysis showed that, out of 15 states that did not require people to wear masks in public, 14 had high COVID-19 rates. Meanwhile, eight states had self-reported adherence rates of 75 percent of greater, and none of these states had a high COVID-19 rate. States with the lowest adherence rates had the greatest likelihood of high COVID-19 rates in the subsequent month. The eight states with at least 75-percent adherence to mask wearing had a mean COVID-19 rate of 109.26 per 100,000 residents in the subsequent month, while the mean COVID-19 rate was 239.99 for states with less than 75 percent adherence. These findings provide new evidence in support of mask-wearing as a major factor that contributes to reduced COVID-19 rates. They suggest that policies and public health efforts to reduce the spread of COVID-19 should include a focus on improved mask adherence throughout the U.S.
Chicago, Ill. (March 25, 2021) – The Alden Network announced the promotion of Cyeria Brown, BSN, RN to Regional Nurse Consultant. As a new graduate in 2014, Brown was hired as a staff nurse at Alden Debes Rehabilitation and Health Care Center in Rockford, Illinois. Because of her integrity, passion for patient safety and her dedication to clinical excellence, she was promoted to Assistant Director of Nursing in 2017 and in less than a year was promoted to Director of Nursing. In her new role as Regional Nurse Consultant, Brown will focus on regulatory compliance, clinical outcomes and the provision of care, programs and services and will identify opportunities to improve patient care and safety throughout her assigned region of post-acute and rehabilitation facilities. Brown obtained her associate of applied science degree from Kishwaukee College and later obtained her bachelor’s degree in nursing from Chamberlain College of Nursing where she is currently pursuing her master’s degree. Additionally, she is licensed by the State of Illinois as a Registered Nurse and is a certified Infection Preventionist. For more than 50 years, The Alden Network has provided health care and residential solutions for seniors and has helped them function to the best of their ability and live life as independently as possible. To learn more about The Alden Network, please call 1-800-291-5900 or visit www.thealdennetwork.com.
Study author and board-certified dermatologist encourages the public to get vaccinated Newswise — ROSEMONT, Ill. (April 7, 2021) — As COVID-19 vaccination ramps up globally, new research published today in the Journal of the American Academy of Dermatology demonstrates the wide variety of skin rashes, including full-body rashes, observed after COVID-19 vaccination. The authors provide reassurance that these reactions are generally mild, resolve on their own, and should not deter the public from getting vaccinated. “We understand that some of these reactions may look scary, but when they appear more than four hours after receiving the COVID-19 vaccine, they are typically minor and in some cases, may indicate the body’s immune system is doing a good job of responding to the vaccine,” says senior study author and board-certified dermatologist Esther Freeman, MD, PhD, FAAD, director of Global Health Dermatology at Massachusetts General Hospital and principal investigator of the international COVID-19 Dermatology Registry. “Some rashes may appear a day or two after vaccination, and some have a delayed onset, as long as 7-14 days after vaccination. Most of these rashes resolve on their own with time or — depending on the rash — may require oral antihistamines, topical steroids, or other treatments as directed by a physician.” Dr. Freeman does note that any reactions that start immediately after vaccination, or within four hours of the shot, need to be taken very seriously, and patients experiencing these rare type of allergic symptoms should seek prompt medical attention, as recommended by the CDC. Dr. Freeman’s research examined the Moderna and Pfizer vaccines — two of the most widely administered vaccines authorized for emergency use by the FDA — in the U.S. from December 2020 to February 2021. The research of 414 skin reactions logged in the COVID-19 Dermatology Registry from healthcare workers, including board-certified dermatologists, identified a broad range of skin reactions. These include 218 cases of large, delayed reactions near the injection site — dubbed “COVID vaccine arm” — as well as other types of rashes that include rashes at the injection spot, hives, and full-body rashes similar to those typically seen after viral infections. Dr. Freeman also says that some patients have developed pernio/chilblains, or what has been called “COVID toes”, following COVID-19 vaccines. She notes that this is of particular interest because it shows that the vaccine is triggering a similar immune response as can be seen after the virus. While these reactions are uncomfortable, she says, they are not necessarily a bad thing. It shows that your body is mounting an immune response to the vaccine, she says, which, in some cases, shows up on your skin. “As dermatologists, we view the skin as a window into what is happening elsewhere in your body,” says Dr. Freeman. “Through this research, we have a deeper understanding of how the COVID-19 vaccine affects our patients and their skin, and I hope our findings, which show that people tolerated vaccination well even when they did develop skin side effects, offer greater reassurance for anyone who is hesitant to get vaccinated.” In addition to studying a large spectrum of skin reactions to the COVID-19 vaccines, the researchers assessed patients’ responses from the first dose to the second. They found that less than half of the people who experienced skin reactions after the first dose experienced a reaction after the second, and if they did, it was milder. “I hope this information encourages more people to get their second dose of the COVID-19 vaccine even if they experienced a skin reaction after their first dose,” says Dr. Freeman. “The COVID-19 vaccine will help protect you from getting the virus and can also prevent you from getting very sick if you do get infected.” If you have concerns about a rash or other skin reaction that develops after getting the COVID-19 vaccine, don’t hesitate to call your doctor or a board-certified dermatologist. To find a board-certified dermatologist in your area, visit aad.org/findaderm.
Which Senescent Cells Turn On Genes That Encode for Secreted Tumor-regulating Factors Newswise — PHILADELPHIA — (April 1, 2021) — Scientists at The Wistar Institute identified a new mechanism of transcriptional control of cellular senescence that drives the release of inflammatory molecules that influence tumor development through altering the surrounding microenvironment. The study, published in Nature Cell Biology, reports that methyltransferase-like 3 (METTL3) and 14 (METTL14) proteins moonlight as transcriptional regulators that allow for establishment of the senescence-associated secretory phenotype (SASP). Cellular senescence is a stable state of growth arrest in which cells stop dividing but remain viable and produce an array of inflammatory and growth-promoting molecules collectively defined as SASP. These molecules account for the complex crosstalk between senescent cells and neighbouring cells and the effect of cellular senescence in various physiological processes and diseases. Although senescence is regarded as a potent barrier for tumor development, the SASP plays a stage-dependent role during tumor development, mediating the clearance of premalignant lesions during intiation and promoting the growth of established tumors. “Senescent cells undergo widespread changes in gene expression needed to adapt their phenotype and functions,” said Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, Christopher M. Davis Professor and leader of the Immunology, Microenvironment & Metastasis Program. “We pointed out a new mechanism that allows cells to turn on a set of genes encoding for the SASP molecules and may potentially be targeted to inhibit this aspect of senescence while preserving its antitumor function.” Zhang, who is senior author on the study, and his team focused on METTL3 and METTL14, proteins known for chemically modifying messenger RNA to regulate its function. They found a new role of these proteins in senescence and regulation of gene expression that is independent of their RNA-modifying function. Depleting cells of METTL3 and METTL14, researchers observed reduced expression of SASP genes, such as inflammatory cytokines, but no effect on cell cycle arrest or other markers of senescence, indicating that decrease in SASP is not an indirect consequence of overall senescence inhibition. “Our results indicate that METTL3 and METTL14 promote expression of SASP genes, in accordance with other studies that revealed an oncogenic role for these two proteins,” said Pingyu Liu, Ph.D., first author of the study and a staff scientist in the Zhang Lab. The team further analyzed the association of METTL3 and METTL14 with DNA, comparing senescent and control cells. While the two proteins are found together on DNA in control cells, in senescent cells they have different distribution patterns, whereby METTL3 tends to sit upstream of SASP genes, near the transcription start site, while METTL14 binds away from gene bodies, on regulatory elements called enhancers. Researchers demonstrated that through this positioning pattern and interacting with each other, METTL3 and METTL14 bring closer together two DNA sequences that in non-senescent cells are distant, allowing the formation of promoter-enhancer chromatin loops. As a consequence, expression of the SASP genes is turned on. “Although we focused on senescence, we envision that the transcription-regulating function of METTL3 and METTL14 may be involved in many other biological processes beyond our current study,” concluded Zhang. Co-authors: Jianhuang Lin, Takeshi Fukumoto, Timothy Nacarelli, Xue Hao, and Andrew V. Kossenkov from The Wistar Institute; Fuming Li and M. Celeste Simon from University of Pennsylvania. Work supported by: National Institutes of Health (NIH) grants R01CA160331, R01CA163377, R01CA202919, R01CA239128, R01CA243142, P01AG031862 to R.Z., P50CA228991, and R50CA211199; U.S. Department of Defense grants OC180109 and OC190181. Additional support was provided by The Honorable Tina Brozman Foundation for Ovarian Cancer Research and The Tina Brozman Ovarian Cancer Research Consortium 2.0; and Ovarian Cancer Research Alliance (Collaborative Research Development Grant #596552 and Ann and Sol Schreiber Mentored Investigator Award #649658). Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815. Publication information: m6A-independent genome-wide METTL3 and METTL14 redistribution drives senescence-associated secretory phenotype, Nature Cell Biology, 2021. Online publication. Photo: The Wistar Institute Wistar's Dr. Rugang Zhang (center) and lab members
Newswise — CHARLOTTESVILLE, Va., March 29, 2021 – An international team of researchers led by a University of Virginia School of Medicine professor is warning that scientists must better prepare for the next pandemic – and has developed a plan to do just that. Noting the “avalanche” of scientific data generated in response to COVID-19, UVA’s Wladek Minor, PhD, and colleagues are calling for the creation of an “advanced information system” (AIS) to help scientists integrate, monitor and evaluate the vast amounts of data that will be produced as researchers reveal the molecular architecture of the next pathogen posing a big biological threat. This information on the shape, structure and function of a pathogen is essential to the development of medications, vaccines and treatments. For example, the COVID-19 vaccines now available target the “spike” protein on the surface of the SARS-CoV-2 virus. Their heavily cited online resource for COVID-19 (https://covid-19.bioreproducibility.org/) demonstrates the usefulness of their approach and can be used as a foundation for the new research strategy, they say. The site includes carefully validated 3-D structural models of numerous proteins related to the SARS-CoV-2 virus, including many potential drug targets. “Structural models and other experimental results produced by various laboratories must follow a standard evaluation procedure to ensure that they are accurate and conform to accepted scientific standards,” said Minor, Harrison Distinguished Professor of Molecular Physiology and Biological Physics at UVa. “Standardized validation is important for all areas of biomedical sciences, especially for structural models, which are often used as a starting point in subsequent research, such as computer-guided drug docking studies and data mining. Even seemingly insignificant errors can lead such research astray.” Battling a Pandemic One important role of AIS would be to identify structures that can be refined and improved, the researchers say. They were happy to note that inspection of the molecular blueprints produced for components of COVID-19 and deposited in the Protein Data Bank online database suggests that most were very good. Less than 1% needed significant reinterpretation and less than 10% could be optimized by moderate revisions. Still, good buildings require good blueprints. The same is true with vaccines and disease treatments. It’s critical, the researchers say, that the structural and other data for pathogens are as accurate as possible, and that scientists from various fields are speaking the same language when discussing and using them. The proposed AIS would help ensure conformity across disciplines. “Almost 100,000 COVID-19-related papers have been published and over a thousand models of macromolecules encoded by SARS-CoV-2 have been experimentally determined in about a year. No single human can possibly digest this volume of information,” Minor said. “We believe that the most promising solution to information overload and the lack of effective information retrieval is the creation of an advanced information system that is capable of harvesting results from all relevant resources and presenting the information in instructive ways that promote understanding and knowledge.” The researchers acknowledge that implementing their proposal would be a major undertaking. Other resources that sought to offer similar benefits on a smaller scale have already come and gone. That’s why it’s so important, the scientists say, that we act now. “Creating an AIS will undoubtedly require the collaboration of many scientists who are experts in their respective fields, but it seems to be the only way to prepare biomedical science for the next pandemic,” the researchers write in a new scientific paper outlining their proposal. “In the history of humanity, the COVID-19 pandemic is relatively mild by comparison with the bubonic plague (Black Death) that killed a hundred times more people,” the researchers conclude. “We might not be so lucky next time.” New Approach Outlined The researchers – from UVA, the National Cancer Institute, Poland and Austria – have detailed their plan in an article in the scientific journal IUCrJ. The article is featured on the journal cover. The resarch team consists of Marek Grabowski, Joanna M. Macnar, Marcin Cymborowski, David R. Cooper, Ivan G. Shabalin, Miroslaw Gilski, Dariusz Brzezinski, Marcin Kowiel, Zbigniew Dauter, Bernhard Rupp, Alexander Wlodawer, Mariusz Jaskolski and Minor. In their paper, the researchers gratefully acknowledged the financial support of the National Institutes of Health’s National Institute of General Medical Sciences, grant R01-GM132595; the Polish National Agency for Academic Exchange, grant PN/BEK/2018/1/00058/U/00001; the Polish National Science Center, grant 2020/01/0/NZ1/00134; the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; FWF (Austrian Science Foundation), grant P 32821; and the Polish National Science Centre, grant 2018/29/B/ST6/01989. Minor and his longtime collaborator Zbyszek Otwinowski, PhD, of the University of Texas Southwestern Medical Center, were recently awarded the Tadeusz Sendzimir Applied Sciences Award by the Polish Institute of Arts and Sciences of America for their efforts to develop and promote software for biomedical applications in the structural biology field. To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.
Newswise — In spring 2020, when the first wave of the coronavirus pandemic hit Finland, older adults drastically reduced their out-of-home activities. During the period of government restrictions, physical exercise was the most common reason to leave home, a recent study at the University of Jyväskylä Faculty of Sport and Health Sciences finds. "In spring 2020, it was feared that the closure of many activity destinations and the recommendations to avoid close contact with persons from other households put in place by the government would decrease physical activity levels, and thus, negatively affect older adults' physical functional capacity," Senior Researcher Erja Portegijs explains. "According to our research results, this was however, not the case." Throughout the restriction period, physical exercise and walking outdoors, for example, in nature was possible, and even encouraged by the government later in the spring. "This study shows that physical exercise was the most common reason to go out," Portegijs adds. "Otherwise, older participants had few reasons to go out beyond grocery shopping during the first spring of the pandemic." Previous research shows that all activities outside of one's home are beneficial for physical activity. As the reasons to leave home were markedly limited during the first spring of the pandemic, more research is needed to determine the long-term effects on mobility and maintaining functional capacity. "This research is unique, even though it was based on the data of 44 participants only," Portegijs says. "Previously, we did not know where older adults moved and for what reason. Studying where people go to is possible using a map-based questionnaire. This is one of the first studies utilizing such a questionnaire among older adults." As coronavirus-related measures have varied significantly between countries, it is not sure whether these results are generalizable to other countries. In Finland, curfews were not implemented and governmental restrictions were mostly based on recommendations rather than enforced regulations. In 2017 and 2018, a map-based questionnaire was used to collect data on frequently visited activity destinations as part of the larger AGNES study among 75-, 80-, and 85-year-old adults living in Jyväskylä city in Central Finland. In May and June 2020, participants were invited to complete the map-based questionnaire following a postal questionnaire. Only a small portion of participants was able to use digital devices independently and thus to participate. These participants had somewhat better health and function than the others. "As abilities to use digital devices improve among the aging population, the relevance of map-based research methods will further increase," Portegijs reflects. Photo: University of Jyväskylä Physical exercise was the most common reason to leave home during the first wave of the pandemic in 2020.
Newswise — PHILADELPHIA—Hormone drugs that reduce androgen levels may help disarm the coronavirus spike protein used to infect cells and stop the progression of severe COVID-19 disease, suggests a new preclinical study from researchers in the Abramson Cancer Center at the University of Pennsylvania and published online in Cell Press’s iScience. Researchers show how two receptors—known as ACE2 and TMPRSS2—are regulated by the androgen hormone and used by SARS-CoV-2 to gain entry into host cells. Blocking the receptors with the clinically proven inhibitor Camostat and other anti-androgen therapies prevented viral entry and replication, they also showed in lab studies. The findings provide more insight into the molecular mechanisms of the virus but also support the use of anti-androgen therapies to treat COVID-19 infections, which are currently being investigated in clinical trials and have produced promising results. They also support data showing increased mortality and severity of disease among men compared to women, who have much lower levels of androgen. “We provide the first evidence that not only TMPRSS2, which is known to be regulated by androgen, but ACE2 can also be directly regulated by this hormone,” said senior author Irfan A. Asangani, PhD, an assistant professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania. “We also show that the SARS-CoV-2 spike relies on these two receptors to impale and enter cells, and that they can be blocked with existing drugs. That’s important because if you stop viral entry, you reduce the viral load and disease progression.” Camostat is a drug approved for use in Japan to treat pancreatitis that inhibits TMPRSS2. Other anti-androgen therapies, including androgen deprivation therapy used to treat prostate cancer, serve similar functions. Driven by the disparity in COVID-19 rates between men and women, the cancer researchers sought to better understand the role androgen and its receptors played in infections, which has long been known to be a driver of prostate cancer. The researchers performed experiments with a pseudotype SARS-CoV-2, which carries the spike proteins of the virus but not its genome. In mice with significantly reduced androgen levels and cells treated with anti-androgen treatments, the researchers found little to no expression of TMPRSS2 and ACE2, suggesting both are regulated by the hormone. They also observed how inhibiting TMPRSS2 with Camostat blocked priming of the spike for entry into cells. That drug, as well as enzalutamide, an anti-androgen therapy used to treat prostate cancer, also blocked the virus’ entry into lung and prostate cells. Combining these therapies, they found, significantly reduced virus entry into cells. “Together, our data provide a strong rationale for clinical evaluations of TMPRSS2 inhibitors, androgen-deprivation therapy / androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible to prevent COVID-19 progression,” the authors wrote. In March, researchers from Brazil reported preliminary results of 600 hospitalized patients in a clinical trial investigating proxalutamide, a new anti-androgen therapy, for the treatment of COVID-19. The drug reduced mortality risk by 92 percent and shortened the median hospital stay by nine days versus the standard of care, the researchers reported. Next, Asangani and his colleagues will partner with Susan R. Weiss, PhD, a professor of Microbiology and co-director of the Penn Center for Research on Coronaviruses and Other Emerging Pathogens, to investigate the findings further using live SARS-CoV-2, as well as anti-androgen therapies’ ability to block different variants of the virus, which continue to emerge and are often differentiated by their spike proteins. Penn co-authors of the study include Qu Deng, Reyaz ur Rasool, Ronnie M. Russell, and Ramakrishnan Natesan. The study was supported by the National Institutes of Health (R01 CA249210-0), a Department of Defense Idea Development Award, a Conquer Cancer Now Award, and Sarcoma Foundation of America.