Cincinnati Children's Hospital Medical Center

AKRON, Ohio, April 2, 2024 /PRNewswire/ -- Researchers at Akron Children's, Cincinnati Children's, University of Michigan and Dayton Children's Hospital, have found that hypothermic therapy reduces symptom severity after concussion. In a study published in the Clinical Journal of Sport Medicine, researchers found that providing selective surface cooling to specific areas in the head and neck after mild brain injury reduced Sport Concussion Assessment Tool (SCAT5) symptom scores by 14% after initial treatment with pro2cool's hypothermic therapy. After a second treatment using the pro2cool® system, SCAT5 scores were 25% lower than those receiving standard concussion care. Study participants were aged 12-19, had received a concussion within eight days of study enrollment, and were placed in one of two groups: one using the standard treatment of care – rest; and the other receiving two treatments with the pro2cool system. Following the initial evaluation and treatment, the groups were further evaluated at later time points – 72 hours, 10 days, and 28 days – with the second round of treatment occurring at 72 hours. It is the first and only concussion treatment study of this population, and the largest single concussion therapy trial known to date. "Traditionally, ice has been used to reduce pain and swelling in muscle injuries," said Dr. Joseph Congeni, director of sports medicine at Akron Children's and lead study investigator at Akron Children's Rebecca D. Considine Research Institute. "Now, this research – along with our previously published pilot study using pro2cool – has found the same to be true for concussions. Sports-related concussions are a significant problem in children aged 12 to 17 in the U.S. About 80%-90% of sports-related concussion symptoms in adolescents resolve in 17 to 28 days, longer than the seven- to 10-day recovery time for adults. And while safeguards continue to be put in place to prevent concussions, little has been done to change the treatment of care for a concussion when one does happen. Traditionally, adolescent concussions have been treated with brain rest – refraining from strenuous physical and mental tasks – until symptoms resolve. Now, in addition to brain rest, concussion symptoms can be treated with selective hypothermic therapy. "We know from what we see on athletic fields and the feedback we receive from parents and kids that brain rest isn't enough," said Dr. Congeni. "The results of this study show the standard of concussion care can be improved upon." This study has important clinical implications: Adolescents with concussions may benefit from receiving multiple treatments with the pro2cool® system to reduce the severity of their symptoms. The pro2cool system used to deliver the therapy is well-tolerated, indicating an initial positive safety profile absent of major adverse effects. "While this publication marks the end of this particular study, the work has just begun," said Dr. Matthew Smith, staff scientist, Rebecca D. Considine Research Institute at Akron Children's and assistant professor, co-director, Basic and Translational Biomedicine Graduate Program, Northeast Ohio Medical University. "There are a variety of questions left to be explored, for example, 'If we use the device to treat sooner, more often, and for longer, then can we improve/maximize the clinical benefit?' Additionally, understanding how these therapeutic effects are achieved at the biological level will be critical in creating personalized treatment protocols for each patient." TecTraum Inc., the makers of the smart technology pro2cool, supplied the device used in the study, which is currently under review by the U.S. Food and Drug Administration (FDA). Citation: Smith, Matthew A. MS, PhD, McNinch, Neil L. MS, RN, PSTAT, et al. Clinical Journal of Sport Medicine Epub ahead of print January 5, 2024 DOI: 10.1097/JSM.0000000000001198 About Akron Children's Akron Children's is an independent, nonprofit pediatric health care system that has been caring for children since 1890. With two hospital campuses, seven regional health centers, and more than 50 primary and specialty care locations throughout Ohio, we are the only health care system in our region fully dedicated to pediatric care. With our vast network of Akron Children's Pediatrics offices, we offer convenient access to expert pediatric primary care for patients from infancy through young adulthood. From our School-Based Health Care to our Quick Care Online® virtual visits and Akron Children's Anywhere app, we make it easy for today's busy families to find the high-quality care they need. In 2023, our health care system provided nearly 1.4 million patient encounters and employed more than 7,000 employees. Learn more at akronchildrens.org. SOURCE Akron Children's Hospital

Scientists at Cincinnati Children's lead deepest dive yet into the mechanics of blood cell development. They found new treasure. CINCINNATI , March 21, 2024 /PRNewswire/ -- Thanks to an unusual application of game theory and machine learning technology, a large team of scientists led by experts at Cincinnati Children's has published the world's most detailed "atlas" of the many types of stem cells and early progenitors involved in producing human blood from diverse donors. Continue Reading A large team of scientists led by experts at Cincinnati Children’s has published the world’s most detailed “atlas” of the many types of stem cells and early progenitors involved in producing human blood from diverse donors. The team has identified more than 80 distinct subsets of hematopoietic stem and progenitor cells (HSPCs) – early-stage cells that kick off production of mature red cells, white cells and other elements of our complex blood system. Details were published March 21, 2024, in Nature Immunology. "We believe our highly focused capture strategy of the earliest HSPCs, intermediate cell states plus stromal populations, and the most abundant end states provides the deepest view of bone marrow stem and progenitor compartments described to date," the co-authors state. The study was led by co-first authors Xuan Zhang, PhD, and Baobao Song, PhD, and co-corresponding authors Nathan Salomonis, PhD, and H. Leighton Grimes, PhD, all researchers with Cincinnati Children's. Overall, the study includes 26 co-authors from four academic medical centers and two biotech companies. Leukemia implications and more This complex research project involved using multiple advanced genomic research tools and computational methods to build detailed genomic and proteomic profiles of more than 300,000 bone marrow cells collected from a diverse mix of donors spanning race and sex. Cincinnati Children's is committed to promoting inclusivity and addressing population diversity in scientific studies as part of their ongoing mission. In addition to meticulous single-cell RNA sequencing work and matching flow cytometry, analyzing the massive data set required innovative use of machine learning technology and dipping into game theory to perform key statistical analyses. Some of the research tools the team used, including two software tools scTriangulate and pyIninityFlow, were developed at Cincinnati Children's. Among the team's key findings: Mixing a new "cocktail" of 132 antibodies that can target surface proteins on HSPCs and related cells. Testing demonstrated that the new mix outperforms commercial products for profiling human bone marrow cells. Identifying 89 clusters by a novel integration of gene expression and surface proteins helped reveal new stem/progenitor cell populations. Strategies and markers for isolating novel cell populations. First, two novel surface markers C5L2 and TSPAN33 to identify cells entering transitional states between progenitor status and becoming a mature neutrophil. Second, distinct staging of human red blood cell formation called erythroblasts with CD326 and CD235a. New online computational tools to predict the cellular origins and possible causes of cancers such as acute myeloid leukemia (AML). "Our analysis uncovers previously hidden cell states, such as the most primitive stem cells, by combining information from diverse prior atlases, surface markers and genes, and new advances in machine learning," Salomonis says. One of the most immediate potential applications of the new stem cell atlas centers on how treatment centers monitor patients receiving therapies for leukemia. "For example, some people develop resistance to Venotoclax with azacytidine (a chemotherapy that was approved in 2018 as a first line therapy for AML)," Grimes says. "In some cases, the therapy-resistant disease appears to be driven by a "monocytic" form of leukemia stem cell (m-LSC) rather than a more "primitive" form (p-LSC). With an atlas like this, it becomes more possible to determine which types of cancer stem cells are present in the AML, and that information could then inform how a clinician might adjust a treatment regimen." The new study reports finding 69 antibodies within 23 cell states that may represent attractive biomarkers for clinical monitoring of people with AML. While the development of the new stem cell atlas is an essential start, much more research and development will be needed to integrate the new data about blood cell formation into medical care, Grimes says. Making the tool available The co-authors predict that the new digital bone marrow atlas will accelerate the discovery of more cellular and molecular regulators of blood diseases. To support such efforts, the research team is making its data and tools widely available to the research community. While the Nature Immunology article has been made open access, full detail and access to this advanced digital resource, including data viewers, methods, raw data and code, are available at . About the study In addition to the first and corresponding authors, contributing co-authors from Cincinnati Children's include Guangyuan Li, Dan Schnell, Kairavee Thakkar, Michal Kouril, Kang Jin, Stuart Hay, and Sidharth Sen, all with the Division of Biomedical Informatics; plus Kyle Ferchen, Bailee Kain, David Bernardicius, Siyuan Ma, and Sierra Bennett, all with the Division of Immunobiology. Data acquisition for this study included support from the Research Flow Cytometry Core and the DNA Sequencing and Genotyping Core at Cincinnati Children's. Contributors also included scientists from the Yale School of Medicine, University of Pittsburgh, University of Colorado School of Medicine, San Diego-based BioLegend Inc., and Massachusetts based Curiox Biosystems, Inc. Funding sources for this work include several grants from the National Institutes of Health, especially an RC2 grant from the NIDDK, complemented by an NIDDK Cooperative Centers of Excellence in Hematology grant, a Specialized Center of Research (SCOR) grant from the Leukemia & Lymphoma Society, and the US Department of Veterans Affairs. SOURCE Cincinnati Children's Hospital Medical Center

Cincinnati Children's-led research team details how bone marrow response in mice varies by stress type and by type of bone, opening new paths for treating blood cancers, infections and more CINCINNATI, March 20, 2024 /PRNewswire/ -- Imagine being able to count the different types of blood cells being formed inside the tiny bones of a mouse and pinpointing the strings and clusters of cells within the bone marrow that are responsible for producing specific types of blood cells. Continue Reading New study in the journal Nature, led by experts at Cincinnati Children's, reveals unprecedented cell-by-cell detail of how the bone marrow's blood production process works, and how different forms of stress affect production sites. That's exactly what a team of scientists led by experts at Cincinnati Children's achieved in a far-reaching study published March 20, 2024, in the prestigious journal Nature. Their work adds unprecedented new understanding of the "elegant" and "resilient" anatomy of bone marrow while also generating evidence of unexpected variations in how the skeleton responds to stresses such as infection or blood loss. "Stunningly, we found that the response to hematopoietic insults varies across the skeleton. We speculate that certain bones have specialized to preferentially respond to some insults, and this will be the focus of future studies," the co-authors state. The research was led by co-first authors Qingqing Wu, PhD, and Jizhou Zhang, PhD, and corresponding author Daniel Lucas, PhD, all with the Division of Experimental Hematology and Cancer Biology at Cincinnati Children's. Overall, 23 researchers from five institutions contributed to this groundbreaking study. The discovery of specific blood cell production sites within the bone marrow raises new challenges and opportunities for diagnosing and treating a number of blood-related conditions. "For example, our data shows that biopsies that draw marrow from just one type of bone may not provide a full picture of how the blood production system has been affected by a disease or other insult," Lucas says. "Meanwhile, efforts to stimulate production of certain blood cell types may be dramatically improved by focusing on specific bone types." Highlights of the findings The key discoveries reported in the paper include: New tools allowing visualization of blood production inside the bone, allowing defining the basic anatomy of blood cell formation. These revealed that bone marrow functions are highly responsive and durable, but not uniform. The paper describes how strings and clusters of cells form within the marrow to act as blood cell production factories. Location matters, even during normal blood cell production. The team demonstrated that different key types of progenitor cells move through different microenvironments as they mature. These microenvironments significantly influence which types of mature blood cells get produced. Different microenvironments give rise to oxygen-carrying red blood cells versus infection-fighting white blood cells, and so on. Unexpected variations in stress responses. The researchers compared how the system responded to three acute kinds of stress: blood loss, L. monocytogenes infection, and granulocyte-colony stimulating factor (G-CSF) treatment (often given to boost white blood cell production after chemotherapy). They also measured how aging changed the process. The team meticulously measured how different bones responded to these insults. Among several examples: blood loss triggered rapid red blood cell production in the sternum, tibia, vertebrae, and humerus -- but not in the skull. Blood loss also temporarily reduced the number of B cell production sites across the skeleton. Meanwhile, when exposed to G-CSF, long bones rapidly increased formation of granulocyte progenitors and mature neutrophils. But in sharp contrast, the sternum from the same mice displayed "profound reductions" in these cell types as well as loss of neutrophil production sites. "These variations are important because until now, mouse studies of blood cell biology have depended almost entirely upon material collected from the femur and tibia," Lucas says. Innovation required just to conduct the study The research team first needed to conduct a research project-within-the-project to establish a method for imaging and counting the different cell types at work within the mouse bone marrow. Counting the cells involved a process called confocal imaging microscopy. This uses specialized microscopes relying on lasers to detect specific tags in the cells. When "tagged" properly, the cells emit different colors under the laser, which allows them to be imaged and counted. The challenge is coming up with the right tag so that the laser accurately detects the targeted cells of interest, while not counting other cells. In this study, the team started with a vast library of potential markers, then they whittled the list down to 35 promising genetic markers Ultimately, they found that detecting cells that express the gene marker ESAM, in combination with other markers, allowed distinguishing between six different types of blood progenitor cells. The marker also proved capable of showing information about the microenvironment, such as whether blood cell production was occurring within sinusoids or arterioles, two distinct types of blood channels found within bone marrow. Importantly, the process developed for this study allowed the team to analyze blood cell development in multiple parts of the skeleton. Next steps Looking ahead, Lucas says much more research will be needed to fully detail how different parts of the skeleton become specialized producers of specific blood components. Also, more studies will be needed to confirm how much of the bone marrow stress response observed in mice also occurs in humans. It will likely require several years of development, but understanding more about the mechanics of blood cell production may allow a wide range of improvements in the precision and effectiveness of treatments to support healthy blood cell production. "It might even allow to build artificial bones capable of producing red blood cells for transfusion," Lucas says. About the study Achieving these findings required significant support from the Bio-Imaging Analysis Facility and the Research Flow Cytometry Core at Cincinnati Children's. In addition to Wu, Zhang and Lucas, Cincinnati Children's co-authors included: Sumit Kumar, Siyu Shen, Morgan Kincaid, Courtney B. Johnson, Yanan Sophia Zhang, and Shelli Homan, Marie Dominique Filippi, PhD, and H. Leighton Grimes, PhD, all with Experimental Hematology and Cancer Biology; Anastasiya Slaughter, Benjamin Weinhaus, and Baobao Song from the Immunology Graduate Program; Bryan Sherman, Tzu-Yu Shao, and Sing Sing Way, MD, PhD, from Infectious Diseases; and Matt Kofron, PhD, a member of Developmental Biology and director of the Bio-Imaging and Analysis Facility. The study also included contributions from researchers with the Charles P. Lin lab at Massachusetts General Hospital, Harvard Medical School, and Keisuke Ito at the Albert Einstein College of Medicine in Bronx, NY. The study was supported with funds from several grants from the National Institutes of Health. Individual co-authors also receive support from the Leukemia and Lymphoma Society, the Edward P. Evans Foundation, the HHMI Faculty Scholar's Program, the Burroughs Wellcome Fund, and the March of Dimes Foundation Ohio Collaborative. SOURCE Cincinnati Children's Hospital Medical Center