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Tag: Newswise

  • Chemical exposure in households may decrease pregnancy likelihood, study finds.

    Chemical exposure in households may decrease pregnancy likelihood, study finds.

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    Newswise — Exposure to phthalates, a group of plasticizing and solvent chemicals found in many household products, was linked to a lower probability of getting pregnant, but not to pregnancy loss, according to research by a University of Massachusetts Amherst environmental and reproductive epidemiologist.

    The study, published this week in the journal Environmental Health Perspectives, also noted an association between preconception exposure to phthalates and changes in women’s reproductive hormones, as well as increased inflammation and oxidative stress.  

    “Phthalates are ubiquitous endocrine disruptors and we’re exposed to them every day,” says lead author Carrie Nobles, assistant professor of environmental health sciences in the School of Public Health and Health Sciences.

    Phthalates are found in such common products as shampoo, makeup, vinyl flooring, toys and medical devices. People are exposed primarily by ingesting food and liquid that has come in contact with products containing the chemicals, according to a Centers for Disease Control and Prevention fact sheet. 

    Nobles and team analyzed data from a “unique cohort” of women in the preconception time-to-pregnancy study known as EAGeR (Effects of Aspirin in Gestation and Reproduction), which evaluated the effect of low-dose aspirin on live-birth rates. The study includes detailed information on 1,228 participants during six menstrual cycles when they are attempting to get pregnant. The women who became pregnant were followed through pregnancy.

    “We were able to look at some environmental exposures like phthalates and how that relates to how long it takes to get pregnant. There was detailed data for each menstrual cycle, so we had a good handle on the date of ovulation and the timing of pregnancy when that happened,” Nobles says. 

    The body breaks down phthalates into metabolites that are excreted in urine and can be analyzed. The researchers measured 20 phthalate metabolites in urine samples taken when the participants enrolled in the study.

    “We found there were three parent compounds that seem to be most strongly associated with taking longer to get pregnant, although we saw a general trend toward it taking longer to get pregnant across the phthalates we looked at,” Nobles says. “As exposure got higher, we saw more and more of an effect.”

    The researchers also looked at a global marker of inflammation, C-reactive protein, and found the women who had higher levels of phthalates exposure also had higher levels of inflammation and oxidative stress, which can lead to organ and tissue damage and ultimately to disease. 

    In addition, women who showed higher levels of phthalates had lower estradiol and higher follicle-stimulating hormone across the menstrual cycle, which play an important role in ovulation and the early establishment of pregnancy. 

    “This profile – estradiol staying low and follicle-stimulating hormone staying high – is actually something that we see in women who have ovarian insufficiency, which can happen with age as well as due to some other factors,” Nobles says. “Ovulation just isn’t happening as well as it used to.”

    While women can check consumer product labels and look for phthalate-free options, the ubiquitous nature of the chemicals makes it difficult for an individual to control their exposure.

    In Europe, certain phthalates are banned or severely restricted in their use, but the U.S. has no formal prohibitions. Nobles says the research findings add to the evidence that phthalates exposures have a negative impact on women’s reproductive health and can be used to help inform policy making.

    “Maybe we want to think differently about our regulatory system and how we identify important exposures that are having adverse effects on whether people can get pregnant and have a healthy pregnancy,” Nobles says.  

     

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    University of Massachusetts Amherst

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  • Immune cells shape lungs prenatally, offering novel respiratory disease treatments.

    Immune cells shape lungs prenatally, offering novel respiratory disease treatments.

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    Newswise — Immune cells play an active and intimate role in directing the growth of human lung tissue during development, researchers find, revolutionising our understanding of early lung development and the role of immune cells outside of immunity.

    The research offers new insights for understanding and treating respiratory conditions, such as chronic obstructive pulmonary disease (COPD). Respiratory conditions account for almost 20 per cent of all deaths in children under five years worldwide1.

    The work reveals a surprising coordination between the immune and respiratory systems, much earlier in development than previously thought. This discovery raises questions about the potential role of immune cells in other developing organs across the body.

    Researchers from the Wellcome Sanger Institute, University College London (UCL) and their collaborators at EMBL’s European Bioinformatics Institute used advanced single-cell technologies to map the development of early human lung immune cells over time.

    This study has created a first-of-its-kind immune cell atlas of the developing lung2. It is part of the international Human Cell Atlas3 initiative, which is mapping every cell type in the human body, to transform our understanding of health, infection and disease.

    The findings, published today (15 December) in Science Immunology, will help shed light on the mechanisms behind childhood lung diseases.

    Immune cells make up a substantial portion of the airways and mature lungs, which have critical gas exchange and barrier functions, providing protection against infection of the respiratory tract. However, the roles of immune cells in the developing organ have remained unexplored compared to structural or lining cell types. Recent discoveries confirm the presence of immune cells in human lungs as early as five weeks into development4.

    To explore whether the immune system might influence how lungs grow, the team studied immune cells in early human lungs from 5 to 22 weeks of development. They used various techniques, including single-cell sequencing and experiments with lung cell cultures, to see if immune cells could affect lung cell development.

    They identified key regulators of lung development, including signalling molecule IL-1β and IL-13 that facilitate the coordination of lung stem cells differentiating into specialised mature cell types5.

    The researchers detected an infiltration of innate, followed by adaptive immune cells. Innate cells included innate lymphoid cells (ILCs), natural killer (NK) cells, myeloid cells and progenitor cells. With respect to adaptive immune cells, as well as T cells, both developing and mature B lineage cells were detected, indicating that the lung environment supports B cell development.

    The findings fundamentally change the understanding of the immune and epithelial interactions that are crucial for foetal lung maturation. They also suggest that early immune disturbances could manifest as paediatric lung disease.

    These new insights into mechanisms in early lung formation will also contribute to the development of new therapeutic approaches for regenerating damaged lung tissue and restoring lung function.

    Dr Peng He and Dr Jo Barnes, co-first authors of the study at the Wellcome Sanger Institute and EMBL’s European Bioinformatics Institute, and UCL Division of Medicine respectively, said: “By adopting a focused strategy in mapping the immune system, we reveal a symbiotic relationship between immune cells and developing lungs. These detailed insights open the door to potential regenerative therapies in not only the lung, but in other vital human organs.”

    Dr Marko Nikolić, senior author of the study at UCL Division of Medicine and honorary consultant in respiratory medicine, said: “We now know immune-epithelial crosstalk is a feature of early lung development. This vital baseline of healthy lung development will help us understand what happens when lung developmental processes get disrupted, for example in preterm births, which can lead to respiratory deficiencies.”

    Dr Kerstin Meyer, senior author of the study at the Wellcome Sanger Institute, said: “The active participation of immune cells expands the possibilities for understanding and addressing impaired lung formation. What is super exciting about this mechanism is that it may well apply in other organ systems too.”

    Dr Sarah Teichmann, senior author of the study at the Wellcome Sanger Institute and Co-founder of the Human Cell Atlas, said: “If we are to fully understand the root causes of disease, we require a complete view of cells at all stages in the human body. This important contribution towards a comprehensive Human Cell Atlas will be a valuable reference for studying lung diseases.”

    ENDS

    Notes to Editors:

    1. https://www.who.int/data/gho/indicator-metadata-registry/imr-details/3147
    2. The researchers analysed human embryonic and foetal lung tissue between 5 and 22 weeks post-conception. Human embryonic tissue was provided by the Joint MRC/Wellcome Trust Human Developmental Biology Resource (www.hdbr.org)
    3. The Human Cell Atlas (HCA) is an international collaborative consortium which is creating comprehensive reference maps of all human cells—the fundamental units of life—as a basis for understanding human health and for diagnosing, monitoring, and treating disease. The HCA is likely to impact every aspect of biology and medicine, propelling translational discoveries and applications and ultimately leading to a new era of precision medicine.
      The HCA was co-founded in 2016 by Dr Sarah Teichmann at the Wellcome Sanger Institute (UK) and Dr Aviv Regev, then at the Broad Institute of MIT and Harvard (USA). A truly global initiative, there are now more than 3,100 HCA members, from 98 countries around the world. https://www.humancellatlas.org
    4. https://www.cell.com/cell/fulltext/S0092-8674(22)01415-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867422014155%3Fshowall%3Dtrue
    5. Experimentation showed that IL-1β, a cytokine produced by immune cells, directly induced airway epithelial progenitor cells to differentiate into mature lung lining cells. They do this by decreasing SOX9 expression and proliferation, driving lung epithelial progenitor cells to stop self-renewal.

    Publication:
    J.L. Barnes et al. (2023) ‘Early human lung immune cell development and its role in epithelial cell fate.’ Science Immunology. DOI: 10.1126/sciimmunol.adf9988

    Funding:
    This research was supported by Wellcome. For full funding acknowledgements, please refer to the publication.

    Selected websites:

    About UCL (University College London)
    UCL was founded in 1826. We were the first English university established after Oxford and Cambridge, the first to open up university education to those previously excluded from it, and the first to provide systematic teaching of law, architecture and medicine. We are among the world’s top universities, as reflected by performance in a range of international rankings and tables. UCL currently has over 39,000 students from 150 countries and over 12,500 staff. Our annual income is more than £1 billion. www.ucl.ac.uk | Follow us on Twitter @uclnews | Watch our YouTube channel YouTube.com/UCLTV

    The Wellcome Sanger Institute
    The Wellcome Sanger Institute is a world leader in genomics research. We apply and explore genomic technologies at scale to advance understanding of biology and improve health. Making discoveries not easily made elsewhere, our research delivers insights across health, disease, evolution and pathogen biology. We are open and collaborative; our data, results, tools, technologies and training are freely shared across the globe to advance science.

    Funded by Wellcome, we have the freedom to think long-term and push the boundaries of genomics. We take on the challenges of applying our research to the real world, where we aim to bring benefit to people and society.

    Find out more at www.sanger.ac.uk or follow us on Twitter, Instagram, Facebook, LinkedIn and on our Blog.

    About Wellcome
    Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, infectious disease and climate and health. https://wellcome.org/

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    Wellcome Trust Sanger Institute

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  • Triggering positive points crucial for climate crisis resolution.

    Triggering positive points crucial for climate crisis resolution.

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    Newswise — Positive tipping points must be triggered if we are to avoid the severe consequences of damaging Earth system tipping points, researchers say.

    With global warming on course to breach 1.5oC, at least five Earth system tipping points are likely to be triggered – and more could follow.

    Once triggered, Earth system tipping points would have profound local and global impacts, including sea-level rise from major ice sheet melting, mass species extinction from dieback of the Amazon rainforest and disruption to weather patterns from a collapse of large-scale ocean circulation currents.

    The new commentary – published in One Earth by researchers from the Global Systems Institute at the University of Exeter – says positive tipping points must be triggered to help reach the levels of decarbonisation required. 

    “One reason for hope is that many of the tipping thresholds that are likely to be crossed first are so-called slow tipping systems, which can be briefly exceeded without a commitment to tipping,” said lead author Dr Paul Ritchie.

    “However, rapid decarbonisation that minimises the distance of any overshoot and – even more importantly – limits the time spent beyond a threshold is critical for avoiding triggering climate tipping points.”

    Dr Jesse Abrams said: “One mechanism for achieving the rapid decarbonisation levels required is ironically through positive tipping points, moments when beneficial changes rapidly gain momentum.”

    The research team point to the sales seen in electric vehicles, particularly across Scandinavia, as evidence for the capability of human systems exhibiting positive tipping points.

    Professor Tim Lenton added: “Under the correct enabling conditions, such as affordability, attractiveness and accessibility, Norway have managed to transition the market share of electric vehicles from under 10% to near 90% within a decade.”

    The article is entitled: “Tipping points: Both problem and solution.”

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    University of Exeter

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  • Mathematical framework for evolutionary developmental dynamics (evo-devo).

    Mathematical framework for evolutionary developmental dynamics (evo-devo).

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    Newswise — Natural selection acts on phenotypes constructed over development, which raises the question of how development affects evolution. Classic evolutionary theory indicates that development affects evolution by modulating the genetic covariation upon which selection acts, thus affecting genetic constraints. However, whether genetic constraints are relative, thus diverting adaptation from the direction of steepest fitness ascent, or absolute, thus blocking adaptation in certain directions, remains uncertain. This limits understanding of long-term evolution of developmentally constructed phenotypes. Here we formulate a general, tractable mathematical framework that integrates age progression, explicit development (i.e., the construction of the phenotype across life subject to developmental constraints), and evolutionary dynamics, thus describing the evolutionary and developmental (evo-devo) dynamics. .The framework yields simple equations that can be arranged in a layered structure that we call the evo-devo process, whereby five core elementary components generate all equations including those mechanistically describing genetic covariation and the evo-devo dynamics. The framework recovers evolutionary dynamic equations in gradient form and describes the evolution of genetic covariation from the evolution of genotype, phenotype, environment, and mutational covariation. This shows that genotypic and phenotypic evolution must be followed simultaneously to yield a dynamically sufficient description of long-term phenotypic evolution in gradient form, such that evolution described as the climbing of a fitness landscape occurs in “geno-phenotype” space. Genetic constraints in geno-phenotype space are necessarily absolute because the phenotype is related to the genotype by development. Thus, the long-term evolutionary dynamics of developed phenotypes is strongly non-standard: (1) evolutionary equilibria are either absent or infinite in number and depend on genetic covariation and hence on development; (2) developmental constraints determine the admissible evolutionary path and hence which evolutionary equilibria are admissible; and (3) evolutionary outcomes occur at admissible evolutionary equilibria, which do not generally occur at fitness landscape peaks in geno-phenotype space, but at peaks in the admissible evolutionary path where “total genotypic selection” vanishes if exogenous plastic response vanishes and mutational variation exists in all directions of genotype space. Hence, selection and development jointly define the evolutionary outcomes if absolute mutational constraints and exogenous plastic response are absent, rather than the outcomes being defined only by selection. Moreover, our framework provides formulas for the sensitivities of a recurrence and an alternative method to dynamic optimization (i.e., dynamic programming or optimal control) to identify evolutionary outcomes in models with developmentally dynamic traits. These results show that development has major evolutionary effects.

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    University of St. Andrews

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  • Rembrandt innovated by infusing canvas with lead for The Night Watch.

    Rembrandt innovated by infusing canvas with lead for The Night Watch.

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    Newswise — New research has revealed that Rembrandt impregnated the canvas for his famous 1642 militia painting ‘The Night Watch’ with a lead-containing substance even before applying the first ground layer. Such lead-based impregnation has never before been observed with Rembrandt or his contemporaries. The discovery, published today in Science Advances, underlines Rembrandt’s inventive way of working,  in which he did not shy away from using new techniques.

    The surprising observation is yet another result from Operation Night Watch, the largest and most wide-ranging research and conservation project in the history of Rembrandt’s masterpiece. It resulted from advanced analysis of an actual paint sample taken from the historical painting. First author of the paper is Fréderique Broers, a researcher at the Rijksmuseum and PhD student with professors Katrien Keune (University of Amsterdam), Koen Janssens (University of Antwerp) and Florian Meirer (Utrecht University). Her research forms part of the research project 3D Understanding of Degradation Products in Paintings of the Netherlands Institute for Conservation+Art+Science+ (NICAS), funded by the Dutch Research Council NWO. Broers and coworkers employed a combination of x-ray fluorescence and ptychography to identify and visualize sub-microscale chemical compounds in the lower layers of the canvas. By sampling the small Night Watch paint fragment at DESY (Deutsches Elektronen-Synchrotron, Hamburg), they discovered the lead-rich layer below the quartz-clay ground layer of the canvas. 

    Protection against moisture

    It was already known from earlier studies that Rembrandt had used a quartz-clay ground on the Night Watch. In earlier paintings he had used double grounds, consisting of a first ground containing red earth pigments followed by a second lead white containing ground. The large size of The Night Watch may have motivated Rembrandt to look for a cheaper, less heavy and more flexible alternative for the ground layer. Another issue he had to overcome was that the large canvas was intended for a damp outer wall of the great hall of the Kloveniersdoelen (musketeers’ shooting range) in Amsterdam. It had been reported that under humid conditions the common method of preparing the canvas using animal glue could fail. A contemporary source on painting techniques written by Théodore de Mayerne suggested impregnation with lead-rich oil as an alternative. This may have inspired Rembrandt for his unusual impregnation procedure to improve the durability of his masterpiece.

    Computational imaging

    The presence of this lead-containing ‘layer’ was discovered by the first-ever use of correlated x-ray fluorescence and ptychographic nano-tomography on a historical paint sample. This was performed at the PETRA III synchrotron radiation source at DESY. X-ray fluorescence is used to investigate the distribution of relatively heavy elements (calcium and heavier). Ptychography, a computational imaging technique based on experimentally obtained datasets, is capable of visualizing even the lightest elements and organic fractions. 

    Analysis of the micro sample taken from The Night Watch revealed that on the side of the sample closest to the canvas support a homogenous layer of dispersed lead was present in the ground layer. Since lead components were not to be expected in the quartz-clay ground layer, this was a rather puzzling observation. The results were then combined with the lead distribution map of the full Night Watch, obtained by X-ray fluorescence scanning of the painting in the Rijksmuseum’s Gallery of Honour. This map reveals the presence of lead throughout the painting and suggests application using large semi-circular brushstrokes, supporting the assumption that it results from an impregnation procedure. Even an imprint of the original strainer onto which the canvas was stretched when the preparatory layers were applied, is visible in the lead distribution map. This brings us yet another step closer to understanding Rembrandt’s creative process in painting The Night Watch, as well as its current condition. 

    Publication details

    Fréderique T.H. Broers, Ige Verslype, Koen W. Bossers, Frederik Vanmeert, Victor Gonzalez, Jan Garrevoet, Annelies van Loon, Esther van Duijn, Anna Krekeler, Nouchka De Keyser, Ilse Steeman, Petria Noble, Koen Janssens, Florian Meirer, Katrien Keune: Correlated x-ray fluorescence and ptychographic nanotomography on Rembrandt’s The Night Watch reveals unknown lead “layer”. Science Advances, 15 December 2023. DOI: 10.1126/sciadv.adj9394

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    Universiteit van Amsterdam

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  • Menstrual products contain endocrine disruptors: tampons, pads, liners.

    Menstrual products contain endocrine disruptors: tampons, pads, liners.

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    Newswise — The average menstruator will use over 11,000 tampons or sanitary pads in their lifetime. Vaginal and vulvar tissue that touch pads and tampons is highly permeable. Through this permeable tissue chemicals are absorbed without being metabolized, which makes endocrine-disrupting chemicals potentially dangerous when found in menstrual products. Endocrine-disrupting chemicals can interfere with human hormones and cause medical issues, including gynecological conditions such as endometriosis and uterine fibroids. 

    Joanna Marroquin, a Mason PhD in Public Health student, and Associate Professor Anna Pollack, reviewed studies conducted since 2103 that measured chemicals in menstrual products and that measured human biomarkers of chemical exposure and determined that endocrine-disrupting chemicals were found in menstrual products including tampons, pads, and liners. 

    “Identifying chemicals in menstrual products that menstruators regularly use is important because exposure through these products can impact menstruators’ reproductive health,” said Marroquin, the paper’s first author.  

    The study found that menstrual products contain a variety of endocrine-disrupting chemicals including phthalates, volatile organic compounds, parabens, environmental phenols, fragrance chemicals, dioxins and dioxin-like compounds. 

    This issue is even more relevant thanks to the Robin Danielson Menstrual Product and Intimate Care Product Safety Act of 2023, which was introduced in the U.S. House of Representatives in October 2023. The Act would establish a program of research regarding the risks posed by the presence of dioxins, phthalates, pesticides, chemical fragrances, and other components in menstrual products and intimate care products. 

    This literature reviewed 15 papers published between 2013 and 2023 that tested menstrual products in the U.S., Japan, and South Korea. The researchers note that there are few publications available that measure chemicals in menstrual products.  

    Additionally, though forever chemicals (PFAS) have been found in menstrual underwear, there is a lack of peer-reviewed research on menstrual underwear and other newly-popular-in-the-U.S. products such as menstrual cups and discs. 

    Chemicals in menstrual products: A systematic review was published in BJOG, an international journal of obstetrics and gynecology in September 2023. Additional authors include Marianthi-Anna Kiomourtzoglou from Mailman School of Public Health, Columbia University and Alexandra Scranton from Women’s Voices for the Earth.  

    The research was supported by Pollack’s National Institute of Environmental Health Sciences R01ES31079 award.  

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    George Mason University

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  • From Lecture to Dialogue: How Brief Training Improves Med Students’ Communication

    From Lecture to Dialogue: How Brief Training Improves Med Students’ Communication

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    Newswise — (Boston)—Teaching is an integral communication skill central to the practice of medicine. The art of teaching extends beyond disseminating information. The skill directly translates to health provider-patient communication, the success of which is positively correlated with improved patient outcomes.

     

    “Teaching is a large part of medicine – patient education is critical to providing high quality patient centered care. Education helps patients understand the ‘why’ and ‘what’ of their treatments and allows them to be better participants in their own care, and in shared decision making,” said author Susan White, MD, assistant professor of obstetrics & gynecology at Boston University Chobanian & Avedisian School of Medicine.

     

    In an effort to foster near-peer inter-professional teaching and teamwork, the school has developed a curriculum using medical students as teaching assistants, called Educational Fellows, to work with students studying to become physician assistants (PA).

     

    “Our Educational Fellows curriculum allows medical students to learn the art of teaching (pedagogy) and learning theory and to practice what they had learned in working with PA students in the classroom,” explains White, who also is director of the Physician Assistant  program at the school. “We expect that the Educational Fellow experience will make those medical students better prepared for patient education.”

     

    White and her colleagues present their experiences and lessons learned from establishing this program that 1) introduces select medical students to PA students in the context of a near-peer teaching framework during pre-clinical training; 2) trains the medical students in best practices of teaching and learning; and 3) provides an additional source of instructors for basic science courses.

     

    White believes the program could be modified for other training programs that use peer-peer or near-peer teaching for tutoring or as teaching assistants. For example, PA students might work with students in nursing or physical therapy to provide tutoring or assistance in lab setting, or PhD graduate students might be teaching assistants for undergraduate courses. He hopes that all graduate level programs in medicine will adopt the curriculum to better prepare their graduates to teach and educate their patients, whether it be bedside nurses teaching patients home care skills or surgeons explaining a complex procedure.

     

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    Boston University School of Medicine

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  • New gene therapy could significantly reduce seizures in severe childhood epilepsy

    New gene therapy could significantly reduce seizures in severe childhood epilepsy

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    Newswise — UCL researchers have developed a new gene therapy to cure a devastating form of childhood epilepsy, which a new study shows can significantly reduce seizures in mice.

    The study, published in Brain, sought to find an alternative to surgery for children with focal cortical dysplasia.

    Focal cortical dysplasia is caused by areas of the brain that have developed abnormally and is among the most common causes of drug-resistant epilepsy in children. It frequently occurs in the frontal lobes, which are important for planning and decision-making. Epilepsy in focal cortical dysplasia is associated with comorbidities, including learning disabilities.

    Although surgery to remove the affected brain malformation is effective, its use is severely limited by the risk of permanent neurological deficit and does not always result in seizure freedom.

    Consequently, researchers at the UCL Queen Square Institute of Neurology evaluated a gene therapy based on the overexpression of a potassium channel which regulates neuronal excitability in a mouse model of focal cortical dysplasia in the frontal lobe.

    Potassium channels control the movement of potassium ions in and out of cells. When there is an overexpression of a potassium channel, it means that there is greater regulation, resulting in the decrease of the activity of cells and, in turn, stopping seizures.

    Co-corresponding author, Professor Gabriele Lignani (UCL Queen Square Institute of Neurology), said: “It is very exciting to see that this new gene therapy could potentially be used as an effective alternative to surgery in patients with focal cortical dysplasia.”

    Gene therapies have previously been shown to work in another form of epilepsy where seizures arise in the temporal lobes, but have not been tested in focal cortical dysplasia.

    In this case, the researchers introduced an engineered potassium channel gene called EKC into the affected frontal lobe of the epileptic mice. For added safety, they used a virus that is unable to replicate in order to carry the potassium channel gene.

    Before giving the treatment, researchers monitored the mice’s brain activity for 15 days. They then injected either the virus carrying the EKC gene or a control virus into the affected brain area. The team then monitored the mice’s brain activity for another 15 days.

    The researchers found that the gene therapy reduced seizures by an average of 87% when compared with the control group, without affecting the mouse’s memory or behaviour.

    Lead author Dr Vincent Magloire (UCL Queen Square Institute of Neurology) said: “Following the successful study in mice, we believe the treatment is suitable for clinical translation, and, taking into account the size of the unmet need, it could be deployed to thousands of children who are currently severely affected by uncontrolled seizures.”

    Co-corresponding author, Professor Dimitri Kullmann (UCL Queen Square Institute of Neurology) added: “Plans for a first in human clinical trial are underway and are planned in the next five years.”

    The research was funded by Great Ormond Street Hospital Children’s Charity (GOSH Charity), the Medical Research Council, Epilepsy Research Institute UK and Wellcome.

     

    Notes to Editors

    For more information, please contact Poppy Tombs, UCL Media Relations. T: +44 (0)7733307596, E: [email protected] 

    Amanda Almacellas Barbanoj, Robert T Graham, Benito Maffei, Jenna C Carpenter, Marco Leite, Justin Hoke, Felisia Hardjo, James Scott-Solache, Christos Chimonides, Stephanie Schorge, Dimitri M Kullman, Vincent Magloire, Gabriele Lignani, Anti-seizure Gene Therapy for Focal Cortical Dysplasia, is published in Brain.

    The DOI for this paper is: 10.1093/brain/awad387

    The following URL will link to the article upon publication: https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awad387

    About UCL – London’s Global University

    UCL is a diverse global community of world-class academics, students, industry links, external partners, and alumni. Our powerful collective of individuals and institutions work together to explore new possibilities.

    Since 1826, we have championed independent thought by attracting and nurturing the world’s best minds. Our community of more than 50,000 students from 150 countries and over 16,000 staff pursues academic excellence, breaks boundaries and makes a positive impact on real world problems.

    The Times and Sunday Times University of the Year 2024, we are consistently ranked among the top 10 universities in the world and are one of only a handful of institutions rated as having the strongest academic reputation and the broadest research impact.

    We have a progressive and integrated approach to our teaching and research – championing innovation, creativity and cross-disciplinary working. We teach our students how to think, not what to think, and see them as partners, collaborators and contributors.  

    For almost 200 years, we are proud to have opened higher education to students from a wide range of backgrounds and to change the way we create and share knowledge.

    We were the first in England to welcome women to university education and that courageous attitude and disruptive spirit is still alive today. We are UCL.

    www.ucl.ac.uk | Follow @uclnews on Twitter | Read news at www.ucl.ac.uk/news/ | Listen to UCL podcasts on SoundCloud | View images on Flickr | Find out what’s on at UCL Minds

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    University College London

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  • ‘Long flu’ has emerged as a consequence similar to long COVID

    ‘Long flu’ has emerged as a consequence similar to long COVID

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    BYLINE: Kristina Sauerwein

    Newswise — Since the COVID-19 pandemic began, extensive research has emerged detailing the virus’s ability to attack multiple organ systems, potentially resulting in a set of enduring and often disabling health problems known as long COVID. Now, new research from Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care System indicates that people hospitalized with seasonal influenza also can suffer long-term, negative health effects, especially involving their lungs and airways.

    The new study comparing the viruses that cause COVID-19 and the flu also revealed that in the 18 months after infection, patients hospitalized for either COVID-19 or seasonal influenza faced an increased risk of death, hospital readmission, and health problems in many organ systems. Further, the time of highest risk was 30 days or later after initial infection.

    “The study illustrates the high toll of death and loss of health following hospitalization with either COVID-19 or seasonal influenza,” said senior author Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University. “It’s critical to note that the health risks were higher after the first 30 days of infection. Many people think they’re over COVID-19 or the flu after being discharged from the hospital. That may be true for some people. But our research shows that both viruses can cause long-haul illness.”

    The findings are published Dec. 14 in The Lancet Infectious Diseases.

    The statistical analysis spanned up to 18 months post-infection and included a comparative evaluation of risks of death, hospital admissions and 94 adverse health outcomes involving the body’s major organ systems.

    “A review of past studies on COVID-19 versus the flu focused on a short-term and narrow set of health outcomes,” said Al-Aly, who treats patients within the VA St. Louis Health Care System and is an assistant professor of medicine at Washington University. “Our novel approach compared the long-term health effects of a vast array of conditions. Five years ago, it wouldn’t have occurred to me to examine the possibility of a ‘long flu.’ A major lesson we learned from SARS-CoV-2 is that an infection that initially was thought to only cause brief illness also can lead to chronic disease. This revelation motivated us to look at long-term outcomes of COVID-19 versus flu.

    “We wanted to know whether and to what degree people with flu also experience long-term health effects,” Al-Aly said. “The big answer is that both COVID-19 and the flu led to long-term health problems, and the big aha moment was the realization that the magnitude of long-term health loss eclipsed the problems that these patients endured in the early phase of the infection. Long COVID is much more of a health problem than COVID, and long flu is much more of a health problem than the flu.”

    However, the overall risk and occurrence of death, hospital admissions, and loss of health in many organ systems are substantially higher among COVID-19 patients than among those who have had seasonal influenza, Al-Aly said. “The one notable exception is that the flu poses higher risks to the pulmonary system than COVID-19,” he said. “This tells us the flu is truly more of a respiratory virus, like we’ve all thought for the past 100 years. By comparison, COVID-19 is more aggressive and indiscriminate in that it can attack the pulmonary system, but it can also strike any organ system and is more likely to cause fatal or severe conditions involving the heart, brain, kidneys and other organs.”

    The researchers analyzed de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation’s largest integrated health-care delivery system. They evaluated information involving 81,280 patients hospitalized for COVID-19 at some point from March 1, 2020, through June 30, 2022, as well as 10,985 patients hospitalized for seasonal influenza at some point from Oct. 1, 2015, through Feb. 28, 2019.

    Patients represented multiple ages, races and sexes.

    Regarding both viruses, patient vaccination status did not affect results. Those in the COVID-19 cohort were hospitalized during the pre-delta, delta and omicron eras.

    During the overall 18-month study period, patients who had COVID-19 faced a 50% higher risk of death than those with seasonal influenza. This corresponded to about eight more deaths per 100 persons in the COVID-19 group than among those with the flu.

    Although COVID-19 showed a greater risk of health loss than seasonal influenza, infection with either virus carried significant risk of disability and disease. The researchers found COVID-19 exhibited increased risk of 68% of health conditions examined across all organ systems (64 of the 94 adverse health outcomes studied), while the flu was associated with elevated risk of 6% of health conditions (six of the 94) – mostly in the respiratory system.

    Also, over 18 months, COVID-19 patients experienced an increased risk of hospital readmission as well as admission to an intensive care unit (ICU). For every 100 persons in each group, there were 20 more hospital admissions and nine more ICU admissions in COVID-19 than flu.

    “Our findings highlight the continued need to reduce the risk of hospitalization for these two viruses as a way to alleviate the overall burden of health loss in populations,” Al-Aly said. “For both COVID-19 and seasonal influenza, vaccinations can help prevent severe disease and reduce the risk of hospitalizations and death. Optimizing vaccination uptake must remain a priority for governments and health systems everywhere. This is especially important for vulnerable populations such as the elderly and people who are immunocompromised.”

    In both COVID-19 and the flu, more than half of death and disability occurred in the months after infection as opposed to the first 30 days, the latter of which is known as the acute phase.

    “The idea that COVID-19 or flu are just acute illnesses overlooks their larger long-term effects on human health,” Al-Aly said. “Before the pandemic, we tended to belittle most viral infections by regarding them as somewhat inconsequential: ‘You’ll get sick and get over it in a few days.’ But we’re discovering that is not everyone’s experience. Some people are ending up with serious long-term health issues. We need to wake up to this reality and stop trivializing viral infections and understand that they are major drivers of chronic diseases.”

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    Washington University in St. Louis

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  • Consumers face perplexity with food-date labels, causing confusion in decision-making.

    Consumers face perplexity with food-date labels, causing confusion in decision-making.

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    Consumers grapple with confusion over food-date labels

    Newswise — The use of food-date labels such as “use-by” and “best if used by” causes consumer confusion that results in many Americans discarding food that is safe to eat or donate, according to the November 2023 Consumer Food Insights Report.

    The survey-based report out of Purdue University’s Center for Food Demand Analysis and Sustainability assesses food spending, consumer satisfaction and values, support of agricultural and food policies and trust in information sources. Purdue experts conducted and evaluated the survey, which included 1,200 consumers across the U.S. 

    The Congressional Research Service recently reported that 7% of all U.S. food waste is because of date labeling confusion. “The goal of this month’s CFI survey was to gather consumer perceptions about what these food date labels mean,” said the report’s lead author, Joseph Balagtas, professor of agricultural economics at Purdue and director of CFDAS.

    The USDA Food Safety and Inspection Service defines “use-by” and “best if used by” as references to peak food quality rather than the date after which the food is no longer safe to eat. However, there is no official standard for food date labeling in the U.S., which leads to an unsurprising mix of responses as to what they mean.

    “Over half of consumers connect “best if used by” and “use-by” dates with food safety, while over 30% believe these labels are related to food quality,” Balagtas said. “This information problem is a kind of market failure and leads to waste.

    “One potential fix to misinformation is for the government to set standards for food date labels to help inform consumers what is and is not safe to eat to help reduce food waste in the U.S. The recently proposed Food Date Labeling Act is an attempt to achieve that goal.”

    The November survey also looked at consumer perceptions of foodborne illness risks. Food-risk attitudes are divided into three groups: risk-averse, risk-neutral and risk-loving. The groupings were based on respondents’ self-assessed risk tolerance for food at home (FAH) and food away from home (FAFH) on a scale from 0 (risk-averse) to 10 (fully prepared to take risks or risk-loving). The summaries broken down this way focus on CFI data from January to November 2023.

    “We found that consumers believe the risk of contracting a foodborne illness is higher when eating food at a restaurant compared to eating food they prepare at home themselves, which is consistent with data on the incidence of foodborne illness,” Balagtas said. “So it is not surprising that we also see that consumers who are more risk-averse when it comes to their food, eat home-cooked meals more frequently than consumers willing to take more risks with their food consumption.”

    A variety of store-bought goods have the potential to contain foodborne bacteria that cause illness. Even so, consumers were more likely to select raw meat items as foods that pose a high risk of foodborne illnesses.

    “We see a gap of more than 20 percentage points in the rate at which raw meats were selected compared to leafy greens, milk, flour and raw fruits and vegetables, despite the fact that some of these items that are perceived as ‘safer’ have caused foodborne illness outbreaks in the past,” Balagtas noted.

    The Interagency Food Safety Analytics Collaboration, a group tasked with monitoring the causes of foodborne illnesses in the U.S., recently reported that the contribution of fresh produce to foodborne outbreaks is comparable to that of raw meats, and in some cases, greater.

    The November survey also showed that food insecurity has dropped slightly for the fifth straight month, to 12.6%. “We do observe higher rates of food insecurity among risk-loving consumers, though this difference is likely the result of the correlation between age and food risk attitudes,” said Elijah Bryant, a survey research analyst at the center and co-author of the report.

    Generally, older consumers with more resources, on average, tend to be more food secure and less willing to take food risks, while younger people more willing to take risks tend to have fewer resources, resulting in higher rates of food insecurity.”

    Consumers also were asked to recall their food behaviors over the last month. “Those who are classified as risk-loving reported eating fruits and vegetables without washing them, eating rare or undercooked meat and eating raw dough or batter more frequently than those who are risk-averse,” Bryant said.

    Consumers less willing to take risks with their food were also less likely to agree with claims about the health benefits of non-conventional food items. These claims include organic being more nutritious than non-organic, plant-based milk is healthier than dairy milk and gluten-free food is healthier than products containing gluten.

    This may be indicative of risk-averse consumers being more resistant to alternative foods in the food system that stray from what they perceive as the norm, Bryant said.

    The Center for Food Demand Analysis and Sustainability is part of Purdue’s Next Moves in agriculture and food systems and uses innovative data analysis shared through user-friendly platforms to improve the food system. In addition to the Consumer Food Insights Report, the center offers a portfolio of online dashboards.

    Writer: Steve Koppes

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    Purdue University

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  • Psychology expert available to discuss new “Social Media and Adolescent Health” report

    Psychology expert available to discuss new “Social Media and Adolescent Health” report

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    The National Academies of Sciences, Engineering, and Medicine released a new report Wednesday, Dec. 13, on the mental and physical health effects from social media on adolescents. Written by a committee of 11 experts, “Social Media and Adolescent Health,” provides a comprehensive overview of the latest research related to platform design, transparency and accountability, digital media literacy among young people and adults, and online harassment. 

    Douglas A. Gentile, one of the committee members and Distinguished Professor of psychology at Iowa State University, is available to discuss the findings and recommendations.

    “The science documents that there are valid reasons to be concerned about social media and adolescent health, but we are not powerless. There are steps we can take as a country that will help us maximize the benefits while minimizing the potential harms of social media,” says Gentile.

    For the “Social Media and Adolescent Health” report, Gentile made significant contributions to the sections on addiction and problematic use and the chapter on education and training for teachers and physicians, which recommends:

    • The U.S. Department of Education should draw national attention to the importance of comprehensive digital media literacy and state boards of education should set standards for the same in grades K through 12.
    • The Council for the Accreditation of Educator Preparation should set requirements for digital media literacy education for student teachers and as part of ongoing professional development for veteran teachers. Teacher training interventions should be designed to allow for rigorous evaluation to measure their effectiveness.
    • The Liaison Committee on Medical Education, the Accreditation Commission for Education in Nursing, the Commission on Collegiate Nursing Education, and the Council on Social Work Education should incorporate training on the multiple effects of social media on children’s and adolescents’ well-being into professional education.

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    Iowa State University

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  • Decoding Diabetes: Can Epigenetics Hold the Key?

    Decoding Diabetes: Can Epigenetics Hold the Key?

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    Newswise — Do epigenetic changes cause type 2 diabetes, or do the changes occur only after a person has become ill? A new study by researchers at Lund University provides increased support for the idea that epigenetic changes can cause type 2 diabetes. The researchers behind the new findings published in Nature Communications now aim to develop methods for disease prevention.

    We inherit our genes from our parents, and they seldom change. However, epigenetic changes that arise due to environmental and lifestyle factors can affect the function of genes.

    “Our new extensive study confirms our previous findings from smaller studies, showing that epigenetic changes can contribute to the development of type 2 diabetes. In this study, we have also identified new genes that impact the development of the disease. Our hope is that with the help of these results, we can develop methods that can be used to prevent type 2 diabetes,” says Charlotte Ling, professor of diabetes and epigenetics at Lund University’s Diabetes Centre (LUDC), who led the study.

    The same epigenetic changes

    The researchers studied epigenetics in insulin-producing cells from donors and found 5584 sites in the genome with changes that differed between 25 individuals with type 2 diabetes and 75 individuals without the disease. The same epigenetic changes found in people with type 2 diabetes were also found in individuals with elevated blood sugar levels, which increase the risk of developing the disease.

    “Those of us who study epigenetics, have long tried to understand whether epigenetic changes cause type 2 diabetes or if the changes occur after the disease has already developed. Because we saw the same epigenetic changes in people with type 2 diabetes and individuals at risk for the disease, we conclude that these changes may contribute to the development of type 2 diabetes,” says Tina Rönn, lead author and researcher at LUDC.

    The study identified 203 genes with different expression in individuals with type 2 diabetes compared to the control group. The researchers found that the gene RHOT1 showed epigenetic changes in people with type 2 diabetes and that it also played a key role in insulin secretion in insulin-producing cells. When they knocked out the gene expression of RHOT1 in cells from donors without type 2 diabetes, insulin secretion decreased.

    “When we examined the same type of cells in rats with diabetes, we found a lack of RHOT1, confirming the gene’s importance for insulin secretion,” says Tina Rönn.

    Methods that can prevent the disease

    One goal of the research is to develop a blood-based biomarker that can predict who is at risk of developing type 2 diabetes. Therefore, the researchers investigated whether their results from insulin-producing cells in the pancreas were reflected in the blood of living people. They found epigenetic changes in the blood of a group of 540 people without the disease and they linked this to the future development of type 2 diabetes in half of the individuals.

    Factors such as unhealthy diet, sedentary lifestyle, and ageing increase the risk of type 2 diabetes, and they also affect our epigenetics. With the new study, researchers have identified new mechanisms that may make it possible to develop methods to help prevent type 2 diabetes.

    “If we succeed in developing an epigenetic biomarker, we can identify individuals with epigenetic changes before they become ill. These individuals can, for example, receive personalised lifestyle advice that can reduce their risk of disease, or we can develop methods that aim to correct the activity of certain genes using epigenetic editing,” says Charlotte Ling.

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  • ASH 2023 Tip Sheet From Sylvester Comprehensive Cancer Center

    ASH 2023 Tip Sheet From Sylvester Comprehensive Cancer Center

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    EMBARGOED

    Newswise — Many physician-scientists and other researchers from Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine will be making oral or poster presentations or participating in panel discussions at the American Society of Hematology’s 2023 annual meeting in San Diego, Dec. 9-12.

    Below is an EMBARGOED summary highlighting several presentations involving Sylvester physicians and other staff members.

    Please note that all information is strictly embargoed until the date and time of each presentation. 

    Lymphomas

    984 Limited Duration Loncastuximab Tesirine with Rituximab Induces High Complete Metabolic Response Rate in High-Risk Relapsed/Refractory Follicular Lymphoma — a Phase 2 Study

    EMBARGOED UNTIL Monday, December 11, 2023: 5:45 PM, Grand Hall C

    Presenting Author: Juan Pablo Alderuccio, MD, Sylvester Comprehensive Cancer Center

    Intro: No standard-of-care exists for treatment of relapsed/refractory follicular lymphoma (FL) with worse prognosis in those demonstrating progression of disease within 24 months from frontline immunochemotherapy. Loncastuximab tesirine (loncastuximab) is an antibody-drug conjugate comprising a monoclonal antibody. The authors report results of a single-institution, investigator-initiated study evaluating this combination for the first time to treat FL. Conclusion: A limited duration program combining loncastuximab with rituximab in patients with FL is well tolerated and highly effective for high-risk patients or those with high disease burden.

    615 Chimeric Antigen Receptor (CAR) T Cell Infusion for Large B Cell Lymphoma in Complete Remission: A Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

    EMBARGOED UNTIL Sunday, December 10, 2023: 5:00 PM

    Presenting Author: Trent Wang, DO, MPH, Sylvester Comprehensive Cancer Center

    Intro: There are limited reported outcomes of patients with large B-cell lymphoma (LBCL) who are infused with CD19 CAR-T cells while being in radiographic or metabolic complete remission (CR). The authors hypothesize that these patients in complete remission before CAR-T infusion may have favorable progression-free survival with lower toxicity.

    Conclusion: CAR-T cell in LBCL patients who are CR after receiving two or more lines of prior therapy is a reasonable consolidation option, with a subset of patients remaining progression-free at two years. Their 9% rate of non-relapse mortality highlights the importance of continued follow-up.

     

    1032 Five Year Outcomes of Patients with Large B-Cell Lymphoma Treated with Standard-of-Care Axicabtagene Ciloleucel: Results from the US Lymphoma CAR-T Cell Consortium

    EMBARGOED UNTIL Monday, December 11, 2023: 5:45 PM

    Presenting Author: Jay Y. Spiegel, MD, FRCPC, Sylvester Comprehensive Cancer Center

    Intro: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. The authors previously reported outcomes for axi-cell patients treated with standard-of-care therapy, including 42% who were ineligible for the ZUMA-1 trial. Now, they update outcomes for this cohort at 58 months.  

    Conclusion: This multicenter, retrospective study showed similar five-year results to the ZUMA-1 trial, despite including patients ineligible for that trial due to comorbidities. It supports the curative potential of axi-cel therapy but highlights the risk for non-relapse mortality in this group.

     

    383 Risk of Transformation by Frontline Management in Follicular Lymphoma and Marginal Zone Lymphoma: A US Population-Based Analysis

    EMBARGOED UNTIL Saturday, December 9, 2023: 5 PM

    Presenting Author: Jorge A. Florindez, MD, University of North Carolina School of Medicine

    Sylvester Authors: Izidore S. Lossos, MD, and Juan Pablo Alderuccio, MD

    Intro: Some patients with follicular or marginal zone lymphoma experience high-grade transformation (HGT) into diffuse large B-cell lymphoma. This study used population-based data to assess incidence and risk factors for HGT, post-HGT overall survival and lymphoma-specific survival across subtypes with treatment or surveillance as initial strategies.  

    Conclusion: Frontline treatment was associated with lower risk for HGT in follicular lymphoma, with advanced stage and female gender identified as risk factors. For other lymphomas, initial treatment neither diminished HGT risk nor improved survival afterward. 

     

    Myelodysplastic Syndromes/Neoplasms

    998 Data-Driven Harmonization of 2022 WHO and ICC Classifications of Myelodysplastic Syndromes/Neoplasms (MDS): A Study By the International Consortium for MDS (icMDS)

    EMBARGOED UNTIL Monday, December 11, 2023: 4:45 PM

    Presenting Author: Luca Lanino, MD, Humanitas Clinical and Research Center, Milano, Italy

    Sylvester Authors: Mikkael A. Sekeres, MD, Justin Taylor, MD and Stephen D. Nimer, MD

    Intro: Significant discrepancies still exist between WHO and ICC classifications of myelodysplastic syndromes/neoplasms, despite their recent inclusion of gene mutations and chromosomal abnormalities to enhance diagnosis and clinical decision-making. These differences potentially cause inconsistent practices within the clinical setting. This study for the International Consortium for MDS adopted a data-driven model to develop a harmonization road map for these classifications.

    Conclusion: The study demonstrated the value of this approach based on advanced statistical methods to generate harmonized MDS classifications.

     

    750 Bromodomain and Extra-Terminal Inhibitor INCB057643 (LIMBER-103) in Patients with Relapsed or Refractory Myelofibrosis and Other Advanced Myeloid Neoplasms: A Phase 1 Study

    EMBARGOED UNTIL Monday, December 11, 2023: 11:45 AM

    Presenting Author: Justin Watts, MD, Sylvester Comprehensive Cancer Center

    Intro: Bromodomain and extra-terminal (BET) proteins regulate expression of critical oncoproteins associated with myelofibrosis (MF) and other blood-cancer malignancies, including B-lymphoma-2. This ongoing Phase 1, dose-escalation study is evaluating the safety and tolerability of a BET inhibitor as monotherapy and in combination with ruxolitinib.

    Conclusion: Monotherapy and combination therapy with ruxolitinib were generally well-tolerated, except for the largest monotherapy amount that caused two dose-limiting toxicities. Dose-finding for both therapies is ongoing to determine the recommended expansion dose.

     

    1872 Olutasidenib Alone or in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Myelodysplastic Syndromes/Neoplasms (MDS)

    EMBARGOED UNTIL Saturday, December 9, 2023: 5:30-7:30 PM, Halls G-H (San Diego Convention Center)

    Senior Author: Justin M. Watts, MD, Sylvester Comprehensive Cancer Center (Presenting author is Jorge Cortes, MD, Georgia Cancer Center, Augusta)

    Intro: Olutasidenib, a small molecule drug that targets a mutation involved in certain cancers and is approved for relapsed and refractory acute myeloid leukemia (AML), was studied in 22 patients with a specific type of myelodysplastic syndromes/neoplasms (MDS).

    Conclusion: In this subgroup of patients in a Phase 1/2 study, the drug – used both alone and in combination with another drug – induced durable remissions in patients with intermediate-, high-, or very high-risk MDS, and the treatment had a tolerable and manageable safety profile.

     

    1860 Correlation between Peripheral Blood and Bone Marrow Somatic Mutations Among Patients with Suspected or Established Myelodysplastic Syndromes from the National MDS Study

    EMBARGOED UNTIL Saturday, December 9, 2023: 5:30-7:30 PM, Halls G-H (San Diego Convention Center)

    Senior Author: Mikkael A. Sekeres, MD, Sylvester Comprehensive Cancer Center (Presenter: Amy E. DeZern, MD, Johns Hopkins University)

    Intro: Myelodysplastic syndromes (MDS) – disorders of blood cells in the bone marrow – may result from mutations in stem cells responsible for blood cell creation. Screening and monitoring of some diseases can be accomplished by assessing mutations in peripheral blood, from a basic blood draw, but because the ability to detect and monitor mutations involved with MDS and related conditions is less certain, guidelines often require invasive bone marrow evaluations instead.

    Conclusion: This study, which included 36 patients, compared results from peripheral blood and bone marrow studies and found that peripheral blood can be used to reliably identify somatic (non-hereditary) mutations in patients with suspected or established MDS and related conditions.

     

    4613 Impact of Type of Hypomethylating Agent (HMA) Used on Outcomes of Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) – A Large, Multicenter, Retrospective Analysis

    EMBARGOED UNTIL Monday, December 11, 2023: 6-8 PM, Halls G-H (San Diego Convention Center)

    Sylvester Co-Authors: Mikkael A. Sekeres, MD, and Namrata Sonia Chandhok, MD, Sylvester Comprehensive Cancer Center (Presenting Author: Jan Philipp Bewersdorf, MD, Memorial Sloan Kettering Cancer Center)

    Intro: This multicenter analysis aimed to provide a better understanding of treatment options for patients with cancers of blood cells in the bone marrow – higher-risk myelodysplastic syndromes/neoplasms (HR-MDS). Two drugs, azacitidine and decitabine, both hypomethylating agents, or HMA, provide the foundation of mainstay, frontline treatments for HR-MDS, but they have not been compared directly in randomized trials.

    Conclusion: This study, involving 1,223 patients, with 919 patients included in the survival analysis, found no significant difference in overall survival or overall responses between the two groups of patients treated with the drugs.

     

    44 Altered RNA Export in SF3B1 Mutants Increases Sensitivity to Nuclear Export Inhibition 

    EMBARGOED UNTIL Saturday, December 9, 2023: 9:45 AM 

    First Presenter: Sana Chaudhry, Sylvester Comprehensive Cancer Center 

    Senior Author: Justin Taylor, MD, Sylvester Comprehensive Cancer Center 

    Intro: About half of MDS patients carry genetic alterations, known as somatic mutations, in spliceosome genes, with SF3B1 being the most commonly mutated one. However, no successful therapy exists to target this pathway. The authors hypothesized that XPO1 inhibition may preferentially affect these mutant cells via splicing, and that high-risk MDS patients with this mutation would have a better response to rational drug combinations with next-generation XPO1 inhibitors. 

    Conclusion: The study provides insight on the mechanisms behind the increased effectiveness of XPO1 inhibition in SF3B1-mutant MDS and leukemia patients. These findings also may contribute to development of potentially beneficial drug combinations. 

     

    Leukemias

    The Future Paradigm of HMA + ven or Targeted Inhibitor Approaches: Sequencing or Triplet Combinations in AML Therapy

    EMBARGOED UNTIL Sunday, December 10, 2023: 4:30-5:45 PM, Room 6CF (San Diego Convention Center

    Presenting Author: Justin M. Watts, MD, Sylvester Comprehensive Cancer Center

    Description: This Education Session will review the transformation in AML therapy from traditional 7+3 for fit patients and hypomethylating agents for unfit patients to new standards of care and ongoing questions in the field. We will discuss the data regarding the development of hypomethylating agents plus venetoclax as the new standard of care for older patients and those not eligible for induction chemotherapy. There is growing interest in the use of HMA/Ven combinations for younger and fit patients and in specific subsets of AML; limited data in these patient populations and ongoing clinical trials will be reviewed. Resistance to HMA/Ven therapy remains a significant concern, and recent data regarding mechanisms of resistance and potential strategies to overcome ven resistance will be addressed. Given the FDA approval of several targeted agents in AML since 2017, there is a need to understand and optimize the use of these medications in combinations with traditional AML therapy. Questions regarding combinations, sequencing and management of toxicities will be discussed. Optimization of 7+3 chemotherapy in specific subsets of AML will be reviewed, including 7+3 based combinations with FLT3 inhibitors or gemtuzumab, as well as the use of CPX-351 in older patients with secondary AML and recent data in other AML patient populations. 

     

    2888 Olutasidenib for the Treatment of mIDH1 Acute Myeloid Leukemia in Patients Relapsed or Refractory to Hematopoietic Stem Cell Transplant, Prior mIDH1 Inhibitor, or Venetoclax

    EMBARGOED UNTIL Sunday, December 10, 2023: 6-8 PM, Halls G-H (San Diego Convention Center)

    Senior Author: Justin M. Watts, MD, Sylvester Comprehensive Cancer Center (Presenter: Jorge Cortes, MD, Georgia Cancer Center, Augusta)

    Intro: Olutasidenib, a small molecule drug approved for treatment of relapsed and refractory acute myeloid leukemia, targets a specific mutation that exists in these cancers. It is being studied in subsets of patients whose disease returned after treatment with stem cell transplant or the drugs ivosidenib (IVO) or venetoclax (VEN). The research team is conducting post-study analyses to better understand the response to olutasidenib in these poor-prognosis subgroups.

    Conclusion: Olutasidenib alone or in combination with a drug called azacitidine may induce complete remissions in patients with this type of AMD or myelodysplastic syndromes/neoplasms (MDS) that was relapsing or refractory to VEN, IVO or even hematopoietic stem cell transplant. This supports further study in larger groups of difficult-to-treat patients.

     

    918 Patient-Reported Outcomes in Acute Myeloid Leukemia Patients with FLT3-ITD Mutation Receiving Quizartinib Vs. Standard Chemotherapy: Results from the Quantum-First Trial – Clinically Relevant Abstract

    EMBARGOED UNTIL Monday, December 11, 2023: 4 PM

    Presenting Author: Esther Natalie Oliva, MD, U.O.C. Ematologia, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy

    Senior Author: Mikkael A. Sekeres, MD, Sylvester Comprehensive Cancer Center

    Intro: QuANTUM-First, a global, Phase 3 clinical trial evaluated the safety and effectiveness of the novel oral inhibitor quizartinib in combination with standard first-line and consolidation chemotherapy, and as a maintenance monotherapy for adults with acute myeloid leukemia (AML). While quizartinib showed clinically meaningful improvements in overall survival, an exploratory endpoint assessed its impact on patient-reported outcomes. The authors report the first longitudinal results of these outcomes.

    Conclusion: Quizartinib showed improvement in overall survival without any detrimental impact on quality of life and symptoms when added to standard chemotherapy, followed by maintenance monotherapy in newly diagnosed AML patients.

     

    Lung Cancer

    2649 Predictors and Timing of Venous Thromboembolism in Lung Cancer

    EMBARGOED UNTIL Sunday, December 10, 2023: 6-8 PM, Halls G-H (San Diego Convention Center)

    Presenter: Thomas Plate IV, MD, Sylvester Comprehensive Cancer Center (all authors affiliated with Sylvester and/or University of Miami)

    Intro: Venous thromboembolism (VTE), the blockage of a blood vessel by a clot, is a common complication in lung cancer, and physicians often prescribe blood thinners for prevention, but there’s uncertainty about true incidence, risk factors and effects of treatments with various subtypes of lung cancer. Sylvester researchers analyzed data from their tumor registry to identify patients diagnosed with lung cancer between 2018 and 2022 and assess venous thromboembolism events and related factors.

    Conclusion: The retrospective study found an increased risk of VTE among patients treated for lung cancer and determined that the development of thrombosis was associated with a significantly decreased overall survival. Every subgroup of patients was at high risk of developing VTE. Statistical analyses showed that VTE and other factors including age, gender, cancer stage, and blood counts were significant predictors of death.

     

    Myeloid Malignancies

    1547 E7820, an Anti-Cancer Sulfonamide, in Combination with Venetoclax in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial

    EMBARGOED UNTIL Saturday, December 9, 2023: 5:30-7:30 PM, Halls G-H (San Diego Convention Center)

    Senior Author: Justin Taylor, MD, Sylvester Comprehensive Cancer Center (Additional Sylvester co-authors: Namrata Sonia Chandhok, MD, [co-first author] and Justin M. Watts, MD) (Presenting author: Jan Philipp Bewersdorf, MD, Memorial Sloan Kettering Cancer Center)

    Intro: Researchers at Sylvester and Memorial Sloan Kettering have studied the effects of an experimental drug, E7820, in patients with relapsing or refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) that result from mutations in certain genes. Preclinical data from their work shows a synergy between E7820 and a drug called venetoclax.

    Conclusion: Based on preclinical data, the researchers plan to amend their current Phase 2 study to include a separate arm of E7820 in combination with venetoclax – a combination that has never been studied in human AML and MDS patients.

     

    Multiple Myeloma

    210 Efficacy and Safety of Daratumumab (DARA) Monotherapy in Patients with Intermediate-Risk or High-Risk Smoldering Multiple Myeloma (SMM): Final Analysis of the Phase 2 Centaurus Study EMBARGOED UNTIL Saturday, December 9, 2023: 3:15 PM, Harbor Ballroom (Manchester Grand Hyatt San Diego) Presenting Author: Ola Landgren, MD, Sylvester Comprehensive Cancer Center Intro: Smoldering multiple myeloma (SMM) is a precursor disorder to multiple myeloma (MM). Current guidelines recommend only active monitoring for SMM, with treatment beginning only when it progresses to MM, but therapeutic intervention at the earlier stage may help delay progression to MM. Investigators in this multicenter collaboration hypothesized that daratumumab (DARA), a monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, could delay progression of SMM to MM. Preliminary results of the Phase 2 CENTAURUS study were previously reported. Here, the researchers present the final analysis. Conclusion: Findings from the final analysis continue to demonstrate the clinical activity of DARA monotherapy in patients with intermediate- or high-risk SMM after a median follow-up of approximately seven years. No new safety concerns were observed.

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  • “Energy Droughts” in Wind and Solar Can Last Nearly a Week, Research Shows

    “Energy Droughts” in Wind and Solar Can Last Nearly a Week, Research Shows

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    Newswise — Solar and wind power may be free, renewable fuels, but they also depend on natural processes that humans cannot control. It’s one thing to acknowledge the risks that come with renewable energy: the sun doesn’t always shine and the wind doesn’t always blow, but what happens when the grid loses both of these energy sources at the same time?

    This phenomenon is known as a compound energy drought. In a new paper, researchers at Pacific Northwest National Laboratory (PNNL) found that in some parts of the country, these energy droughts can last nearly a week.

    “When we have a completely decarbonized grid and depend heavily on solar and wind, energy droughts could have huge amounts of impact on the grid,” said Cameron Bracken, an Earth scientist at PNNL and lead author on the paper. Grid operators need to know when energy droughts will occur so they can prepare to pull energy from different sources. On top of that, understanding where, when, and for how long energy droughts occur will help experts manage grid-level battery systems that can store enough electricity to deploy during times when energy is needed most.

    The team published the findings October 31 in the journal Renewable Energy and will be presenting at this week’s annual meeting of the American Geophysical Union.

    Hunting for cloudy, windless days

    In the past, researchers studied compound energy droughts on a state or regional scale. But not much has been studied on a nationwide scale. To find out more about the risk of energy droughts over the entire continental U.S., the researchers dug into weather data and then used historical energy demand data to understand how often an energy drought occurs when that energy is needed the most.

    The team examined 4 decades of hourly weather data for the continental U.S. and homed in on geographical areas where actual solar and wind energy plants operate today. Weather data included wind speeds at the height of wind turbines as well as the intensity of solar energy falling on solar panels. Times when the weather data showed stagnant air and cloudy skies translated into lower energy generation from the wind and solar plants—a compound energy drought.

    “We essentially took a snapshot of the infrastructure as of 2020 and ran it through the 40 years of weather data, starting in 1980,” Bracken said. “We are basically saying ‘here is how the current infrastructure would have performed under historical weather conditions.’”

    The researchers found that energy droughts can occur in any season across the continental U.S., though they vary widely in frequency and duration. In California, for instance, cloudy and windless conditions might last several days, whereas the same conditions might last for only a few hours in Texas. Utah, Colorado, and Kansas experience frequent energy droughts both over several-hour timescales as well as several-day timescales. The Pacific Northwest and Northeast, meanwhile, seem to experience energy droughts that last several hours more frequently than several days. The different timescales (hourly versus daily) will help inform the energy drought’s impact on the grid—will it last just a few hours, or several days?

    Overall, researchers found that the longest potential compound energy drought on an hourly timescale was 37 hours (in Texas), while the longest energy drought on a daily timescale was six days (in California).

    Energy drought at peak demand

    Simply knowing the where and how of energy droughts is just one piece of the puzzle, Bracken said. He also stressed that a drought of solar and wind power won’t necessarily cause an energy shortage. Grid operators can turn to other sources of energy like hydropower, fossil fuels, or energy transmitted from other regions in the U.S.

    But as the nation aims to move away from fossil fuels and rely more on solar and wind power, grid operators must understand whether energy droughts will occur during times when the demand for electricity might exceed supply. Climate change brings hotter summers and more intense winter storms, and these are times when not only people use more energy to stay safe (for cooling or heating), but access to electricity might mean life or death.

    To understand the possible connection between energy droughts and energy demand, the team mapped their historical, hypothetical generation data onto 40 years of historical energy demand data that also covered real power plants across the continent.

    The data showed that “wind and solar droughts happen during peak demand events more than you would expect due to chance,” Bracken said, meaning that more often than not, windless and cloudless periods occurred during times when demand for power was high. For now, Bracken isn’t certain that the correlation means causation.

    “This could be due to well-understood meteorological phenomenon such as inversions suppressing wind and increasing temperatures, but further study is needed,” Bracken said.

    Energy storage for energy droughts

    Studying patterns in the frequency and duration of energy droughts will also help inform the deployment of long-duration energy storage projects, said Nathalie Voisin, an Earth scientist at PNNL and coauthor on the paper. The paper is the first to provide a uniform standard of what a compound energy drought is and how long it can last in different parts of the country.

    “We’re providing insight on how to adequately design and manage multi-day storage. So when you know an energy drought is going to last for five hours or five days, you can incentivize storage to be managed accordingly,” Voisin said.

    Next, Bracken and the team will extrapolate weather and demand data into the future to see how climate change will affect the frequency and duration of energy droughts. The team plans to model energy droughts all the way to the end of the century combined with evolving infrastructure.

    This research was funded by PNNL through its internal GODEEEP initiative.

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  • Analysis Group Researchers Evaluated Long-Term Patient Experience with Dupilumab Using Groundbreaking Method for Generating Real-World Data

    Analysis Group Researchers Evaluated Long-Term Patient Experience with Dupilumab Using Groundbreaking Method for Generating Real-World Data

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    Newswise — BOSTON, Dec. 12, 2023 /PRNewswire/ — Researchers from Analysis Group, a global leader in health economics and outcomes research (HEOR), have coauthored a follow-up analysis of patient-reported outcomes (PROs) that evaluated outcomes three years after initiation of dupilumab among adults with atopic dermatitis (AD). The study, published in the journal Dermatology and Therapy, extends the one-year results of the previously published RELIEVE-AD study in JAMA Dermatology, which was based on a groundbreaking method for generating real-world data (RWD).

    The study methodology, Longitudinal Surveys of Patients with Recruitment Through Patient Support Programs (LEAP), represents an advance over other RWD approaches, as it engages patients in patient support programs from the time of treatment initiation and tracks individual patient responses to follow-up surveys administered at pre-defined time intervals. This approach provides a true baseline against which to compare longitudinal data over time. This latest edition of the study provides RWD generated through an online survey given at 30–36 months after initiation of treatment, adding to the existing body of data collected at one, two, three, six, nine, and 12 months.

    “Generating real-world data is particularly challenging for conditions like atopic dermatitis that require long-term therapy extending beyond the initial study period. For such chronic conditions, it is important to determine whether long-term treatment creates sustained benefits from the patient’s perspective,” said the study’s senior author, Dr. Alexa B. Kimball, President and CEO at Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center and Professor of Dermatology at Harvard Medical School. “With the LEAP methodology, we were able to effectively identify and evaluate flare-ups, fluctuations in symptoms, and a host of other invaluable RWD points tied to a true baseline with impressive patient participation and, over time, retention.”

    “While clinical trials remain the gold standard for product approval, they are widely recognized as  lacking the type of RWD that regulators, payers, clinicians, and patients want, or require, after a drug’s approval,” said study investigator Min Yang, Vice President at Analysis Group. “LEAP was created to address this problem by generating patient-centric data early after a launch, grounded by a baseline tied to the clinical trial with the ability for longitudinal follow-up and strong retention rates. It’s exciting to be at the forefront of efforts to fill such an important gap, along with Sanofi and Regeneron HEOR researchers, and the clinical experts who were so integral to the success of the LEAP approach.”

    While the methodology, first published in 2021 by JAMA Dermatology following rigorous peer review, was used to better understand patient outcomes with dupilumab – a monoclonal antibody used to treat diseases such as uncontrolled moderate-to-severe AD, certain types of uncontrolled moderate-to-severe asthma, and inadequately controlled chronic rhinosinusitis with nasal polyposis – LEAP is widely applicable across many diseases and condition types.

    “Collecting and synthesizing RWD to generate high-quality evidence is a complex and challenging process, especially when regulators, payers, and clinicians are interested in patient-reported outcomes about diseases and associated therapies,” commented coauthor Eric Q. Wu, Managing Principal at Analysis Group. “Leveraging manufacturers’ programs, such as patient support programs, has proven to be a breakthrough solution for generating early and long-term high-quality RWD.”

    The study, “Long-Term Effectiveness of Dupilumab in Patients with Atopic Dermatitis: Results up to 3 Years from the RELIEVE-AD Study,” was published in August by Dermatology and Therapy. In addition to Dr. Kimball, Dr. Yang, and Dr. Wu, investigators included Dr. Bruce Strober of the Yale School of Medicine; Manager Bruno Martins of Analysis Group; Gaëlle Bégo-Le-Bagousse, Chien-Chia Chuang, and Debra Sierka of Sanofi; and Zhixiao Wang, Brad Shumel, Jingdong Chao, and Dimittri Delevry of Regeneron Pharmaceuticals. Funding was provided by Sanofi and Regeneron.

    To learn more about Analysis Group’s HEOR capabilities, visit www.analysisgroup.com/healthoutcomes. 

    About Analysis Group’s HEOR, Epidemiology & Market Access Practice
    Founded in 1981, Analysis Group is one of the largest international economics consulting firms, with more than 1,200 professionals across 14 offices. Analysis Group’s health care experts apply analytical expertise to health economics and outcomes research (HEOR), clinical research, market access and commercial strategy, and health care policy engagements, as well as drug safety-related engagements in epidemiology. Analysis Group’s internal experts, together with our network of affiliated experts from academia, industry, and government, provide our clients with exceptional breadth and depth of expertise and end-to-end consulting services globally.

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  • Blending the school curriculum to create eco warriors

    Blending the school curriculum to create eco warriors

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    Newswise — They’re among our youngest citizens, but when children learn about sustainability in their own backyard, they’re more likely to protect the environment, say University of South Australia researchers.

    In a citizen science project, UniSA researchers found that when students investigate local sustainability issues, they engage deeply with learning and develop meaningful connections to the environment.

    It’s a vital skill for the next generation, particularly as the world deals with the negative impacts of climate change, waste, and scarcity of resources.

    Now, a new research project, ‘Being Heard: Remixing Critical Literacy for Active Citizenship’, is introducing Year 5 and 6 students to a variety of climate issues through the Climate Ready Schools initiative.

    Conducted at Burton Primary School, the transdisciplinary nature of the project enabled teachers to embed core competencies from the school curriculum, ensuring students achieved required academic outcomes while concurrently developing skills as an environmentally and socially responsible citizen.

    UniSA researchers and Burton Primary School teachers, Bernadette Haggerty and Michelle Miller, say connecting students with local issues is key to building students’ motivation and learning.

    “By working on projects that are close to the students – both physically and emotionally – they’re better able to grasp what the issues are and develop solutions,” Haggerty says.

    “The breadth of projects was amazing – we had students working on beeswax lunch wraps to replace single use plastic, no waste cooking classes to stop food landfill, climate change mitigation by expanding local tree canopy, and even a machine to help plants and animals survive in the desert.

    “Learning about climate change is important for everyone. When we explore sustainability issues in a school setting, we engage the young brain to investigate and find solutions to bigger problems.

    “Students are scaffolded to understand the origins of some of our major disasters like ocean pollution, food waste, plastic pollution. The realisation that pollution starts in their own community, inspires them to take action at the grass roots – at home and the school community.”

    The Burton Primary School project is part of a literacy initiative from UniSA’s Associate Professor Joel Windle, Dr Melanie Baak and Dr David Caldwell, with the Primary Education Teaching Association Australia.

    “Our project encourages student voice and active citizenship. But by tapping into literacy skills from the English curriculum, students concurrently learn multiple skills,” Miller says.

    “It’s all part of creating a transdisciplinary unit of work that enables students to develop knowledge from multiple perspectives. For example, using maths to construct maps, biology to understand the relationship between plants and animals, technology to design solutions, art for sketching, and English for reporting.

    “In this project, students communicated their ideas using literacy skills such as slam poetry, podcasts and YouTube clips. By experimenting with news media, poetry, and film, they learnt different language techniques, skills, and communication approaches.

    “At the same time, they learn how to communicate powerful messages to reduce their ecological footprint, and how to present positive messages to the community.

    “Students have learnt to notice nature, investigate the science, and engineer solutions. They know they can make changes to the world through positive action.”

     

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  • Nanoparticle-Delivered RNA Fights Brain Inflammation

    Nanoparticle-Delivered RNA Fights Brain Inflammation

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    Newswise — Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress expression of a protein linked to excessive inflammation in Alzheimer’s disease.

    In a prior study the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new results, reported in the journal Advanced Materials (impact factor 29.4 ) achieves a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.

     Study co-senior author Li-Huei Tsai, Picower Professor of Neuroscience and Director of The Picower Institute for Learning and Memory and Aging Brain Initiative, said she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, David Koch Institute Professor, who widely known for his seminal work on nanoparticle drug delivery, They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.

     “I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” said Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation who supported this idea without any preliminary evidence.”

    Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a Professor in Chemical Engineering, Biological Engineering and the Koch Institute for Integrative Cancer Research.

    Perfecting a particle

    The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

    Instead the team had to optimize an LNP to do the job. LNPs have four main components and by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.

    Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.

    What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday. 

    A targeted therapy

    Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

    In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.

    “These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.

    The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.

    In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

    “MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.

    In addition to Andresen, Ralvenius, Langer, Tsai and Owen, the paper’s other authors are Margaret Huston, Jay Penney and Julia Maeve Bonner.

    In addition to the The JPB Foundation and The Picower Institute for Learning and Memory, the Robert and Renee Belfer Family, Eduardo Eurnekian, Lester A. Gimpelson, Jay L. and Carroll Miller, the Koch Institute, the Swiss National Science Foundation and the Alzheimer’s Association provided funding for the study.

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    Picower Institute for Learning and Memory at MIT

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  • Should You Take Your Child to the Emergency Room, Urgent Care—or Call the Doctor?

    Should You Take Your Child to the Emergency Room, Urgent Care—or Call the Doctor?

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    Newswise — As a parent, your number one goal is keeping your child safe and healthy. When is it time to head to the emergency department (ED)—and when is it best to call your child’s doctor, or go to an urgent care center?

    When to go to urgent care or call your doctor

    If it’s not an emergency, calling your pediatrician or going to urgent care are the best ways to address a variety of medical concerns. Your pediatrician can advise if you should bring your child in for a visit or take them to urgent care—particularly after hours or on the weekend when the pediatrician’s office isn’t open for visits. Call your doctor or head to urgent care for:

    • A fever lasting more than three days
    • A fever over 102 for more than two days in an infant—without a clear reason for the fever
    • COVID-19 symptoms—including fever, runny nose and dry cough
    • Injury such as sprains, strains or swelling
    • Minor cuts that need stitches
    • Strains and sprains
    • Minor burns that need treatment
    • Diarrhea, nausea or vomiting
    • Bladder infections
    • Coughs, colds and sore throats
    • Sinus pain and earaches
    • Skin problems and rashes

    When to go to the emergency department

    Go to the ED if your child has a severe injury or illness—something that is life-threatening or could cause harm if not treated right away. Head to the ED if your child:

    • Is unusually tired or sleepy, or is acting differently than usual
    • Is in severe, persistent pain
    • Has trouble breathing, or is breathing fast or deep
    • Has an injury that seems severe, such as:
      • A broken bone or injury where the body part looks deformed or out of alignment, there is numbness or a lot of swelling, or the child is in severe pain
      • Bleeding from a large or deep cut, a large cut to the head, chest or abdomen, or bleeding that will not stop after placing pressure for 10 minutes
      • A head injury causing vomiting, a headache, confusion or loss of consciousness
      • A fall from a significant height
    • Ingests a poison, or too much/the wrong medicine:
      • If your child is acting OK, call the Poison Control Center first: 1-800-222-1222.
      • If your child has trouble breathing, collapses or can’t wake up after being poisoned, call 911.
    • Is under 2 months of age with a fever of 100.4 or higher (Call your doctor first.)
    • Has a high fever AND a stiff neck and headache
    • Has a fever AND a widespread purple-red rash
    • Is very dehydrated—diapers are dry, eyes are sunken, child is not peeing—especially after vomiting or diarrhea, or is very weak—can’t move much, drink or talk

    When to call 911

    Sometimes, there’s no time to call the doctor or even drive to the ED. If it’s a life-threatening emergency, when minutes count, call 911. Examples include: 

    • Choking
    • Child is not breathing—or lips are turning blue, purple or gray
    • Your child has a seizure for the first time, or a seizure lasting longer than 5 minutes
    • Child won’t respond, or has passed out
    • Injury to the neck or spine
    • Severe head injury
    • Severe burns, such as from a fire, or burns near the eyes, nose, mouth or groin
    • Severe allergic reaction, with swelling and trouble breathing

    When in doubt, call your doctor

    If it’s not a life-threatening emergency and you’re debating between the ED, urgent care or maybe waiting until the morning—pick up the phone and call your doctor. Most offices have an after-hours line or a nurse or doctor on call who can help you decide.

    Above all, trust your instinct. “I tell parents, if you know in your heart that your child has to go to the ED, just go,” says Christopher Tolcher, MD, FAAP, a pediatrician with Agoura-West Valley Pediatrics—part of the Children’s Hospital Los Angeles Care Network.

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  • Materials Research Institute names 2023 Roy Award winners

    Materials Research Institute names 2023 Roy Award winners

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    Newswise — UNIVERSITY PARK, Pa. — Six Penn State materials researchers have received the 2023 Rustum and Della Roy Innovation in Materials Research Award, covering a wide range of research with societal impact. The award is presented by the Materials Research Institute (MRI) and recognizes recent interdisciplinary materials research at Penn State that yields innovative and unexpected results.  

    The award includes three categories: Early Career Faculty, Non-Tenure Faculty, and Research Staff and Graduate Student. It exists thanks to a gift from Della and Rustum Roy, who are both late alumni of Penn State’s College of Earth and Mineral Sciences and were long-serving faculty in the college.  

    This year’s winners, listed below, were announced at the 2023 Materials Day event in October.  

    Early Career Faculty category

    Amrita Basak, assistant professor of mechanical engineering 

    Basak’s work is built around high-impact transdisciplinary research that addresses the global requirement of sustainable manufacturing in power generation, propulsion, defense, energy storage and construction. For metals, her research group uses laser powder bed fusion and laser directed energy deposition techniques to process high-performance materials such as iron and nickel alloys and oxide-dispersed strengthened alloys. Her research group is also interested in learning what makes certain materials have superior properties and how to use them.  

    “Our research has the potential to improve properties of parts fabricated by 3D printing reducing cost and material wastage,” Basak said. “These would result in higher performance. For example, if we can make parts that can withstand high temperatures, gas turbines’ efficiency would increase.” 

    Elizabeth Elacqua, assistant professor of chemistry 

    Elacqua’s research group focuses on developing ways to synthesize new polymers. This research is nature-inspired and founded on using polymer chemistry to address bottlenecks in organic synthesis and using organic chemistry to address challenges in polymer synthesis. Her group also studies the use of abundant chemicals, such as those left over from the petroleum refining process, to make new rigid, diamond-like polymers. 

    “The polymers we are making thus far have specific applications ranging from light-promoted catalysis to organic semiconductors and high tensile strength materials,” Elacqua said. “While everything is still in its infancy, we can envision accessing polymers that are integral components of future technologies, such as solar cells and composite materials.” 

    Non-Tenure Faculty and Research Staff category  

    Seng Huat Lee, assistant research professor of bulk crystal growth 

    Lee’s research revolves around new quantum materials, unique substances with extraordinary properties that make them of interest for developing faster computers and advanced energy systems. He works to develop new quantum materials with tailored properties, particularly materials that potentially generate new types of quantum technologies. He uses various bulk growth techniques to synthesize and discover emergent quantum phenomena on bulk single crystals, which are crystals that form as a single, uniform piece which gives them unique behaviors. 

    “Government agencies have recognized the importance of developing novel quantum materials,” Lee said. “Quantum materials hold the potential to revolutionize numerous industries, encompassing quantum information science, energy harvesting and telecommunications, by ushering in next-generation technologies.” 

    Wenjie Li, associate research professor of materials science and engineering 

    Li’s research focuses on the development of sustainable and renewable energy conversion materials and devices. One example is converting waste heat energy to useful electricity using thermoelectric materials. This research emphasizes both materials innovation and translation of materials properties to device and system performance to deliver practical solutions. 

    “My research focuses on materials and device innovations to accelerate science-based solutions that solve pressing societal problems in the area of energy, climate and environmental sustainability,” Li said. “My research can ultimately contribute to development of sustainable and renewable energy supplies and decarbonizations that can benefit everyone.” 

    Graduate Student category 

    Sarbashis Das, graduate student in electrical engineering 

    Das’s research includes work to start a 2D materials foundry which will make the high-quality films grown by MRI’s Two-Dimensional Crystal Consortium Materials Innovation Platform available to the commercial marketplace. This was inspired by his participation in the National Science Foundation’s Innovation Corps program, which is for university-based researchers interested in exploring the commercialization potential of their work. His research also involves developing commercial artificial intelligence-aided graphene chemical sensors for use in real-time detection of food spoilage, adulteration and contamination in food processing facilities. 

    “Our efforts will potentially lead to the mainstream adoption of 2D materials and their fascinating properties to solve real-world challenges,” Das said. “The use of 2D materials for real-time food spoilage sensors will enable us to tackle the global problem of food safety in a scalable and sustainable manner. Apart from food, this technology could have broad applications such as real-time monitoring of corrosion in critical infrastructure, which will improve public safety.” 

    Tyus Yeingst, graduate student in biomedical engineering 

    Yeingst’s research focuses on biomaterials, specifically hard polymers, hydrogels and nanoparticles. The applications of these biomaterials are for tissue regeneration and cancer treatment. These materials are controlled using high-intensity focused ultrasound and near-infrared light to properly deliver and release the therapeutics. Along with his Roy Award, he was recognized as one of six Penn State graduate students to win the prestigious National Defense Science and Engineering Graduate Fellowship.

    “Applications for my research include bone regeneration for those suffering from aging, osteomyelitis, cancer and battlefield injuries,” Yeingst said. “Cancer treatment also covers a large base of the population, as everyone knows someone or is someone who has been affected by cancer.” 

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  • Cell Therapy Appears Safe and Effective for Lymphoma in Remission

    Cell Therapy Appears Safe and Effective for Lymphoma in Remission

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    Newswise — MIAMI, FLORIDA (EMBARGOED UNTIL SUNDAY, DEC. 10, 2023 AT 8:00 P.M. ET) – A study led by researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine suggests that CAR-T immunotherapy remains a viable option for patients who have lymphoma that goes into remission before the cell therapy begins.

    While the study doesn’t answer the question of whether cell therapy in remission is the right choice, it does say that it’s not the wrong choice.

    “I don’t think it answers the question of: Should we give these patients cell therapy? But I think it answers the question that we can – that it’s safe and that it’s a reasonable strategy when you’re in that spot,” said Trent Wang, D.O., a Sylvester hematologist and cellular therapy specialist who will present study findings in an oral presentation at the 65th ASH Annual Meeting and Exposition, the American Society of Hematology’s conference taking place in San Diego, California, Dec. 9-12.

    Most patients receiving cell therapy, a form of immunotherapy that uses immune cells engineered to recognize and attack the patient’s cancer, desperately need it. For some, it comes after many other treatments have failed. But Wang noticed an odd phenomenon in the past few years when treating lymphoma patients with this form of therapy: Some of his patients went into complete remission before the cells ever touched their bodies.

    This uncommon scenario occurs during the process of getting to cell therapy, which in the case of Wang’s study uses a kind of engineered immune cell known as CAR-T cells. When a patient starts the process, there’s a waiting period of three to five weeks before they get the treatment. Insurance approval is needed, and the cells themselves need to be manufactured from the patient’s own cells. But many of these patients are very sick with their cancer, so physicians will often treat them with a short course of chemotherapy or other drugs to tamp down the symptoms.

    A small handful of these patients end up in remission during this waiting period treatment, the clinicians have found.

    “That prompted this dilemma: Now what are we supposed to do?” Wang said. “Should we change the plan or give the therapy anyway? We just didn’t have a lot of information on this scenario.”

    Wang said more often than not his team would proceed with the cell therapy in these cases, mainly to prevent yet another stretch of time where the patients’ cancer might come back again. But it didn’t feel like a very informed decision.

    Wang and his colleagues noticed that their patients who received the cells while in remission tended to fare well after their infusion. But they didn’t know if those results would hold up in an analysis of a larger group. They proposed a research study to the Center for International Blood & Marrow Transplant Research, a nationwide registry that tracks patients who have received transplants and/or cell therapies.

    The study included data from 134 patients in the registry who had gone into complete remission in the waiting period before receiving their cell therapy. To find that group, the scientists screened the records for more than 5,000 cell therapy patients.

    They found that this group of patients had a 43% probability of progression-free survival over the two years following their treatment, about the same percentage as patients in the registry who were not in remission when they received CAR-T. However, the patients in remission had very low levels of toxicities related to their cell therapies, namely an immune overreaction known as cytokine release syndrome and neurotoxicity, two side effects that can sometimes accompany CAR-T cell therapy.

    The study used data from patients treated with CAR-T cell therapy between 2015 to 2021, and current frequencies of specific cell therapy use are slightly different from those that were used in practice just a few years ago, Wang said. Next, the researchers want to explore the data paralleling more recent treatment trends.

    Authors: Wang, first author, and Antonio M. Jimenez Jimenez, M.D., last author, are Sylvester researchers. Co-authors include Kwang Wooahn, Ph.D., Manmeet Kaur, and Mehdi Hamadani, M.D., Medical College of Wisconsin; Mazyar Shadman, M.D., Fred Hutchinson Cancer Center, Seattle; Alex F. Herrera, M.D., City of Hope, Duarte, California; and Craig S. Sauter, M.D., Taussig Cancer Institute, Cleveland.

    Conflicts and disclosures: A full list of disclosures is included with the abstract.

    # # #

    Presentation Title: 615 Chimeric Antigen Receptor (CAR) T Cell Infusion for Large B Cell Lymphoma in Complete Remission: A Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis 

    DOWNLOADABLE VIDEO HERE 

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    Sylvester Comprehensive Cancer Center

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