Technologies and strategies reshaping regulatory trends Major regulatory changes in 2025 Future outlook Advancements in drug manufacturing technologies are reshaping global regulatory frameworks. This shift is largely driven by the integration of artificial intelligence (AI)-powered models, cloud-based platforms, and other innovations in drug discovery and development. Looking ahead, this article highlights the key trends expected to shape the regulatory landscape of pharmaceutical manufacturing in 2025. Regulatory agencies—including the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Brazil’s National Health Surveillance Agency (ANVISA)—are responsible for overseeing compliance to ensure that pharmaceutical companies maintain high standards in drug development.1 To meet these expectations, the pharmaceutical industry must adhere to rigorous regulations that safeguard drug effectiveness, safety, and quality throughout the development and manufacturing process. Image Credit: Quality Stock Arts/Shutterstock.com Technologies and strategies reshaping regulatory trends The adoption of artificial intelligence (AI) and large language models (LLMs) is rapidly reshaping clinical research and drug development.2 These advanced tools allow researchers to screen millions of compounds from chemical databases to identify promising therapeutic candidates, significantly reducing the time and cost typically required to explore the vast chemical space. In clinical trials, AI models enhance the selection of patient populations and help predict outcomes, leading to higher success rates for novel drug development.3 However, as AI becomes more embedded in the drug discovery pipeline, regulatory bodies have stepped up efforts to ensure these technologies are integrated safely and ethically. To that end, regulators are increasingly engaging with industry stakeholders to adapt and evolve policy frameworks. Beyond AI, cloud-based technologies are pivotal in modernizing regulatory submissions and data exchange.4 Cloud platforms enable real-time collaboration and offer greater flexibility in product development and lifecycle management. For example, the FDA’s PRISM Project demonstrated how a secure, cloud-based system can streamline regulatory submissions and scientific reviews. Such frameworks have the potential to accelerate approval timelines, ease submission bottlenecks, and encourage international collaboration among regulatory agencies. Despite these advantages, cloud-based systems also raise concerns about data security and intellectual property protection. These risks have prompted regulators to develop more stringent guidelines aimed at safeguarding sensitive information. To support evidence-based decisions, regulatory agencies are also leveraging real-world evidence (RWE). Multiple studies suggest that incorporating RWE into regulatory evaluations has improved the overall quality of decisions on new drug approvals.5 Standardization is another key focus area. Broader adoption of the electronic common technical document (eCTD) format within the International Council for Harmonisation (ICH) framework is helping bring greater consistency to regulatory submissions.6 Standardized documentation not only reduces duplication and minimizes errors but also provides pharmaceutical companies with a more predictable and streamlined submission process. Market Report 2025: Pharmaceutical Manufacturing Major regulatory changes in 2025 In January 2025, the US FDA published a draft regulatory guidance entitled “The Considerations for Use of Artificial Intelligence to Support Regulatory Decision-Making for Drug and Biological Products”.7 The regulatory guidance aimed at formulating a risk-based credibility assessment framework to examine the usefulness of AI models in decision-making about the safety and efficacy of drugs and biological products. The 2025 guidelines also emphasize transparency, data quality, and continuous monitoring. From February 2, 2025, pharmaceutical companies in the European Union (EU) region must comply with AI literacy requirements and avoid AI practices that are prohibited under Article 514. By August 2, 2025, obligations for general-purpose AI models will take effect, which might impact AI-driven drug development and regulatory submissions.8 Corporate Sustainability Reporting Directive (CSRD), an EU directive mandate effective from 2025, requires pharmaceutical companies to disclose environmental, social, and governance (ESG) activities to strengthen transparency in sustainability efforts. The Corporate Sustainability Due Diligence Directive (CSDDD) has been applied in both EU and non-EU pharma companies to promote ethical business practices. This policy was established to foster sustainable and responsible behavior within their supply chains by identifying, preventing, and alleviating adverse impacts on the environment and the general population. The Digital Operational Resilience Act (DORA) is an EU regulation, effective from January 17, 2025, that focuses on ensuring a secure financial system in Europe. DORA ensures strong cybersecurity resilience measures for financial entities for higher transparency in financial transactions and supply chain financing in pharmaceutical companies. In January 2025, another EU regulation-Health Technology Assessment Regulation (HTAR), took effect. This EMA regulation promotes collaboration between regulatory and health technology assessment bodies, thereby accelerating patient access to innovative treatments by harmonizing the evaluation process. This regulation also ensures the high quality of new technology, medical devices, and medicines through coordinated assessments. The FDA encourages pharmaceutical companies to adopt advanced manufacturing technologies (AMTs) to improve the reliability and robustness of the manufacturing process. AMTs would be significantly beneficial because they could reduce drug development time and enhance product quality. FDA’s AMT guidance could also effectively help maintain the supply of drugs that are life-supporting The FDA’s Breakthrough Therapy program and the EMA’s PRIME scheme focus on streamlining approval pathways for ground-breaking therapies. These guidelines could reduce the time required to develop new therapy and enable a quick treatment for unmet medical needs. FDA's Latest Guidelines for Pharma Manufacturing | What's New? Play The CDMO Surge: Why Pharma Is Outsourcing More Than Ever Future outlook 2025 presents the pharma industry with regulatory modernization driven by cloud-based technologies, AI-powered tools, and expanded global harmonization efforts. Regulatory agencies will continue fostering innovation while ensuring patient safety, ethical conduct, and data integrity. Many opportunities are awaiting amidst the uncertainties that emerged due to the implementation of new technologies in drug development. Regulatory frameworks are evolving to adopt new ways of scientific thinking and ensure high-quality treatment. Pharmaceutical leaders must anticipate the changes in the regulatory landscape to stay ahead and quickly integrate compliance strategies into their long-term research and development (R&D) and commercialization plans. Pharma companies that enable quick adaptation to regulatory shifts will have a competitive advantage in launching new therapies to the market faster and more efficiently. References Joppi R, et al. Food and Drug Administration vs European Medicines Agency: Review times and clinical evidence on novel drugs at the time of approval. Br J Clin Pharmacol. 2020;86(1):170-174. doi: 10.1111/bcp.14130. Niazi SK, Mariam Z. Artificial intelligence in drug development: reshaping the therapeutic landscape. Ther Adv Drug Saf. 2025. doi: 10.1177/20420986251321704. Chopra H, et al. Revolutionizing clinical trials: the role of AI in accelerating medical breakthroughs. Int J Surg. 2023;109(12):4211-4220. doi: 10.1097/JS9.0000000000000705. Khalil R, Macdonald JC, Gustafson A, Aljuburi L, Bisordi F, Beakes-Read G. Walking the talk in digital transformation of regulatory review. Front Med (Lausanne). 2023 Jul 26;10:1233142. doi: 10.3389/fmed.2023.1233142. Burns L, et al. Real-world evidence for regulatory decision-making: updated guidance from around the world. Front Med (Lausanne). 2023;10:1236462. doi: 10.3389/fmed.2023.1236462. Macdonald JC, et al. Digital Innovation in Medicinal Product Regulatory Submission, Review, and Approvals to Create a Dynamic Regulatory Ecosystem-Are We Ready for a Revolution? Front Med (Lausanne). 2021 May 21;8:660808. doi: 10.3389/fmed.2021.660808. Considerations for the Use of Artificial Intelligence To Support Regulatory Decision-Making for Drug and Biological Products. Food and Drug Adminidtration.2025. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-artificial-intelligence-support-regulatory-decision-making-drug-and-biological Commission publishes the Guidelines on prohibited artificial intelligence (AI) practices, as defined by the AI Act. European Comissions. 2025. Available at: https://digital-strategy.ec.europa.eu/en/library/commission-publishes-guidelines-prohibited-artificial-intelligence-ai-practices-defined-ai-act Further Reading

What Are CGMs and How Do They Work? Why Non-Diabetics Are Embracing CGMs Commercial Drivers and Technology Startups Scientific Evidence: Are CGMs Useful for the Healthy? Industry Outlook and Future Applications Glucose Monitoring: Friend or Fad? Did you know that even a healthy person’s blood sugar can spike to levels typically associated with prediabetes just from eating a carbohydrate-rich meal?1 Continuous glucose monitors (CGMs) are revealing surprising metabolic insights, and now, non-diabetics are using them to optimize their health like never before. Image Credit: Halfpoint/Shutterstock.com CGMs were initially designed for diabetes management but are increasingly being used by non-diabetic individuals seeking real-time metabolic insights. Interests in athletic performance optimization, weight management, and early metabolic health monitoring drive this trend.2 However, emerging health-tech startups are also capitalizing on this interest, which makes these CGMs easily available but also raises regulatory and medical concerns about the appropriateness of CGM use in healthy individuals. This article explores the scientific validity of non-diabetic CGM use, the commercial landscape, and the future implications of widespread CGM use in health technology. What Are CGMs and How Do They Work? CGMs are wearable biosensors that measure glucose levels continuously in the interstitial fluid. Unlike traditional blood glucose monitoring, CGMs provide real-time data and glucose trend patterns, enabling users to track fluctuations due to diet, exercise, and stress.2 Most CGMs function through a small subcutaneous sensor that transmits glucose readings to a paired electronic device, offering insights without the need for frequent finger-prick tests.3 Recent advancements have led to the development of over-the-counter CGMs, such as the Dexcom Stelo and Abbott Lingo, broadening their accessibility to the general public.4 These devices now offer improved accuracy, longer wear durations, and integration with smartphone applications, enhancing user convenience and data tracking. Additionally, CGM technology continues to improve, with sensors becoming smaller, more accurate, and less invasive, making them more appealing to a broader audience. Some CGM models now incorporate predictive analytics, alerting users to potential glucose fluctuations before they occur. This proactive approach allows individuals to make timely adjustments to their diet or activity levels, further enhancing the utility of CGMs in health optimization.5 Endometriosis Breakthroughs: New Treatments and Research Why Non-Diabetics Are Embracing CGMs While CGMs are undeniably a game-changer for people living with diabetes, several key motivations are also driving the adoption of CGMs among individuals without diabetes. Athletic Performance and Biohacking Athletes and fitness enthusiasts are increasingly using CGMs to optimize their physical performance by tracking glucose stability during exercise. Studies indicate that glucose fluctuations can affect endurance and recovery, and real-time monitoring helps tailor nutritional strategies.6 Moreover, personalized insights into glucose responses to different macronutrients also allow athletes to avoid energy crashes and optimize fueling strategies. Some elite athletes incorporate CGM data to refine carbohydrate intake timing, ensuring stable energy levels throughout training and competition.6 Weight Management and Personalized Nutrition Data obtained from CGMs on postprandial glucose responses are also influencing dietary choices to minimize glycemic spikes. This approach is often marketed as a strategy for preventing metabolic disorders, although the scientific validation for the process remains limited.1,7 Some users adopt low-glycemic diets based on CGM feedback, although concerns exist regarding the potential for unnecessary food restrictions. However, the ability to observe real-time glucose fluctuations also allows users to experiment with different meal compositions to identify the most effective dietary approach for maintaining stable energy levels.7 Early Detection of Metabolic Dysregulation Some consumers use CGMs to identify early signs of insulin resistance or prediabetes. By monitoring long-term glucose patterns, individuals may identify irregular trends that could prompt earlier lifestyle interventions, potentially delaying or preventing metabolic disorders.8 Emerging research also indicates that excessive postprandial glucose fluctuations, even in non-diabetic individuals, may be associated with an increased risk of metabolic dysfunction over time. Monitoring these fluctuations with CGMs allows for a proactive approach to metabolic health by helping individuals recognize trends that could indicate reduced glucose tolerance.1,8 Stress and Sleep Monitoring CGM data can also reveal how stress and sleep deprivation impact glucose levels. Studies indicate that chronic stress and poor sleep can contribute to dysregulated glucose metabolism, making CGM feedback a tool for lifestyle modification.6 Nighttime glucose fluctuations have been linked to hormonal imbalances and poor recovery, and individuals using CGMs may adjust their sleep hygiene and stress management techniques accordingly. Additionally, some individuals are using CGMs in conjunction with wearable fitness trackers to correlate glucose fluctuations with sleep patterns, physical activity, and heart rate variability. This integration offers a more comprehensive view of how lifestyle factors interact with glucose metabolism, supporting targeted interventions to optimize overall well-being.5 The Rise Of Glucose Monitoring Among Non-Diabetics Play Commercial Drivers and Technology Startups With the growing interest in CGMS, especially from a larger consumer base consisting of athletes and fitness enthusiasts, various companies such as Dexcom, and startups such as Levels, Veri, and Nutrisense have invested funds and resources in developing over-the-counter (OTC) CGMS. The first OTC CGM, the Dexcom Stelo Glucose Biosensor System, was approved by the United States (U.S.) Food and Drug Administration (FDA) in March 2024. However, the device is cleared for use only among individuals above the age of 18 who are not suffering from problematic low-sugar conditions or are using insulin to treat diabetes since it is not programmed to send alerts if the blood sugar levels are dangerously low or high.4 This recent FDA approval of OTC CGMs marks a significant shift, enabling broader accessibility while raising concerns about the potential for medical misinformation and unnecessary medicalization of normal glucose fluctuations.4 Some experts also caution that CGMs should not replace standard diagnostic tools for metabolic health, emphasizing the need for appropriate consumer education and regulatory oversight. The Role of Fiber in Preventing Chronic Disease Scientific Evidence: Are CGMs Useful for the Healthy? Despite widespread enthusiasm, the clinical utility of CGMs in non-diabetic individuals remains controversial.7 Several studies have explored their effectiveness across factors such as normal glucose variability, the lack of predictive value in CGM data, and its potential to cause unnecessary anxiety. Research indicates that transient glucose spikes in healthy individuals are common and not necessarily indicative of metabolic dysfunction.7 Individualized responses to different foods vary widely, complicating the use of CGMs for standardized dietary recommendations. Additionally, there is insufficient evidence linking CGM-derived metrics in healthy individuals to long-term health outcomes.8 Scientists believe that without extensive longitudinal studies, CGM data interpretation remains largely speculative. Moreover, some users often misinterpret normal glucose fluctuations as problematic, leading to restrictive eating behaviors and unwarranted concerns about glucose control.7 The psychological impact of constantly monitoring glucose data may lead to orthorexia or excessive dietary rigidity. While CGMs provide valuable data for diabetics, the medical community remains cautious about their use in healthy individuals due to the lack of robust evidence supporting their benefits outside of diabetes management. Industry Outlook and Future Applications However, despite concerns, the CGM market is rapidly evolving, with several key trends shaping its future, including its integration with wearable devices and the incorporation of artificial intelligence (AI)-driven insights. The convergence of CGMs with smartwatches and fitness trackers may enhance their usability and provide multi-metric health insights.2 Devices that combine glucose monitoring with heart rate variability and sleep tracking could also offer a more holistic view of metabolic health. Furthermore, advanced algorithms may improve CGM data interpretation, offering personalized recommendations for metabolic health.3 Machine learning applications could refine glucose response predictions, leading to more actionable insights for users.5 As CGMs become mainstream among non-diabetic users, regulatory bodies may impose stricter guidelines on their marketing and usage.4 The medical community has also called for clearer guidance on CGM applicability in non-diabetic populations to avoid misinterpretation of glucose data. Download your PDF copy now! Glucose Monitoring: Friend or Fad? To conclude, the increasing use of CGMs by non-diabetics reflects the growing interest in personalized health tracking. However, while CGMs provide metabolic insights, their clinical utility in healthy individuals remains unproven. Moreover, emerging startups investing in CGM development and OTC availability are driving commercial growth. Still, regulatory oversight and further scientific research are needed to validate the benefits of CGMs for the general population. Current findings indicate that the future of CGM technology lies in integrating it with broader digital health ecosystems to provide more comprehensive, evidence-based metabolic health solutions. References Jarvis, P. R. E., Cardin, J. L., Nisevich-Bede, P. M., & McCarter, J. P. (2023). Continuous glucose monitoring in a healthy population: understanding the post-prandial glycemic response in individuals without diabetes mellitus. Metabolism: clinical and experimental, 146, 155640. https://doi.org/10.1016/j.metabol.2023.155640

The Liver is a Vital Organ, Crucial to Digestion, Metabolism and the Elimination of Toxins. It has a unique ability, regeneration, which allows it to replace liver cells damaged by the very toxins that these cells eliminate. However, The Liver Stops Regenerating in Cases of Diseases That Involves Chronic Liver Damage -Such as Cirrhosis -. Such Diseases Are Becoming Increasingly Prevalent, Associated with Bad Dietary Habits and Alcohol. Learning to Activate Liver Regeneration is therefore a Priority Today, To Benefit Mainly Patients with Severe Liver Damage and Also Those Who Have Had Part of Their Liver Cut Out to Remove A Tumor. Research at the National Cancer Research Center (CNIO), Published Today in Nature, Has Discovered In Animal Models A Previously Unknown Mechanism of Liver Regeneration. It is a process that is triggered very quickly, just a few minutes after acute liver damage occurs, with the amino acid glutamate playing a key role. The Authors Write in Nature That, In Light Of Their Results, Nutritional Glutamate Supplementation Can Effectively Promote Liver Regeneration and Benefit Patients With Severe and Chronic Liver Damage, Such as Those Recovering After Hepatectomy, Two Stimulates Liver Growth, or Eve Those Awaiting a Translant. As Explained by Nabil Djouder, Head of the Cnio Growth Factors, Nutrients and Cancer Group and Senior Author of the Study, "Unhealthy Diet and Lifestyle Can Affect Liver Regeneration. Our Results Describe A Fundamental and Universal Mechanism That Allows The Liver to Regenerate Acute Damage. ALSO HELP Improve Liver Regenerative Capacity in Patients With Severe Liver Damage, Such as Cirrhosis, or Those Who Have Undergone Partial Resection in Surgery to Remove A Tumor. " The First Author of the Paper is Cnio Researcher María del Mar Rigual. A "Complex and Ingenious" Perspective On Liver Regeneration Liver regeneration was known to occur through the proliferation of liver cells, known as hepatocytes. However, The Molecular Mechanisms Involved Were Not Fully Under Under. This Current Discovery is very novel, as it Describes Communication Between Two Different Organ, The Liver and Bone Marrow, Involving The Immune System. The results show that liver and bone marrow are interconnected by glutamate. After Acute Liver Damage, Liver Cells, Called Hepatocytes, Produce Glutamate and Send it Into The Bloodstream; Through the Blood, Glutamate Reaches The Bone Marrow, Inside the Bones, Where It Activates Monocytes, A Type of Immune System Cell. Monocytes Then Travel to the Liver and Along The Way Become Macrophages - Also Immune Cells. The Presence of Glutamate Reprogrammes The Metabolism of Macrophages, and These Consequently Begin to Secrete A Growth Factor That Leads To An Increase In Hepatocyte Production. In Other Words, A Rapid Chain of Events Allows Glutamate to Trigger Liver Regeneration In Just Minutes, Through Changes in the Macrophage Metabolism. It is, Says Djouder, "A New, Complex and Ingenious Perspective On How The Liver Stimulates Its Own Regeneration." A Specific Population of Hepatocytes Produced Glutamate The Research Also Clarifies A Previously Unanswered Question: How The Various Areas of the Liver Are Coordinated During Regeneration. In the liver, there are different types of hepatocytes, organized in different Areas; The Hepatocytes in Each Area Perform Specific Metabolic Functions. The Study Now Published in Nature Reveals That Hepatocytes Producing A Protein Known As Glutamine Synthetase, which regulates glutamate levels, play a key role in regeneration. According to the Cnio Group, When Glutamine Synthetase is inhibited, there is more glutamate in circulation, which accelerates liver regeneration. This is what happens when the liver suffers acute damage: glutamine synthase activity decreases, blood glutamate Increases, and from there, the connection with the bone marrow is established, reprogramming macrophas and stimulating hepatocyte proliferation. Possible Therapeutic Applications The Experiments have been carried out in animal models, but their results have been tested with bioinformatics tools, using databases of mouse and human hepatocytes. Dietary Glutamate Supplementation May Simply Be Recommended In The Future After Liver Extirpation, and Also to Reduce Liver Damage Caused by Cirrhosis, which is Common in Patients With Poor Diet or Unhealthy Lifestyle or Other Serious Liver Diseases. Factors, Nutrients and Cancer Group and Senior Author of the Study Rigual ALSO SUGGESTS ADDING ANOTHER Goal for Future Research: "Exploring Further The Possibility of Using Glutamate Supplements In Humans Who Have Undergone Liver Resection for Tumor Removal."

The body's cells respond to stress-toxins, mutations, starvation or other assaults-by pausing normal functions to focus on conserving energy, repairing damaged components and boosting defenses. If the stress is manageable, cells resume normal activity; if not, they self-destruct. Scientists have believed for decades this response happens as a linear chain of events: sensors in the cell "sound an alarm" and modify a key protein, which then changes a second protein that slows or shuts down the cell's normal function. But in a new study published today in the journal Nature, researchers at Case Western Reserve University have discovered a cell's response is more nuanced and compartmentalized-not fixed or rigid, as previously thought. The groundbreaking research suggests this adaptive response to stress- which the researchers call "split-integrated stress response" or s-ISR-could potentially be exploited to kill cancer cells and more effectively treat neurodegenerative diseases. Maria Hatzoglou, professor of the Department of Genetics and Genome Sciences at the Case Western Reserve School of Medicine and the study's principal investigator, found for the first time a cell's response to stress can be fine-tuned depending its nature, intensity and duration. This flexibility provides novel insights into how cells in organisms-from yeast to humans-adapt to their environment. This study represents a new way of thinking about cellular stress. ISR is not a one-size-fits-all system like we used to think. Instead, it can change and adjust depending on the type, strength and length of the stress the cell is experiencing." Maria Hatzoglou, Professor, Department of Genetics and Genome Sciences, Case Western Reserve School of Medicine The study The study used mouse models of Vanishing White Matter Disease, which causes progressive degeneration of the brain's white matter in children, leading to neurological problems like motor difficulties, seizures and cognitive decline. Hatzoglou's research revealed that cells carrying the gene causing the disease had mutations in the key protein normally responsible for shutting down operations in the cell under stress. Somehow, the brain cells adapt and mostly function normally but are exceptionally vulnerable, self-destructing even under mild stress. The research team, which included colleagues at Case Western Reserve, McGill University and Karolinska Institute, determined how the cells reacted explains why patients show significant decline in cognitive and motor abilities after relatively minor stressors like fever or mild head trauma. Other late-onset neurodegenerative diseases like multiple sclerosis and amyotrophic lateral sclerosis (better known as ALS) may share a similar mechanism, the researchers said. Diseased brain cells adapt to preserve functions under normal conditions, but modest stressors accelerate decline. Understanding this adaptation to stress could lead to new targets for cancer chemotherapy, Hatzoglou said, because cancer cells respond to stressors like chemotherapy in one of two ways: either self-destruct or mutate to preserve their function, becoming resistant to the treatment. With that knowledge, she said she plans to study chemotherapy-resistant breast cancer cells to better understand how those cells adapt to stress and find new targets for treating disease. The study was funded by the National Institutes of Health, Case Comprehensive Cancer Center, Terry Fox Foundation Oncometabolism Team, Canadian Institutes for Health Research, Swedish Research Council, Swedish Cancer Society and National Multiple Sclerosis Society.

The last time a new class of antibiotics reached the market was nearly three decades ago - but that could soon change, thanks to a discovery by researchers at McMaster University. A team led by renowned researcher Gerry Wright has identified a strong candidate to challenge even some of the most drug-resistant bacteria on the planet: a new molecule called lariocidin. The findings were published in the journal Nature on March 26, 2025. The discovery of the all-new class of antibiotics responds to a critical need for new antimicrobial medicines, as bacteria and other microorganisms evolve new ways to withstand existing drugs. This phenomenon is called antimicrobial resistance - or AMR - and it's one of the top global public health threats, according to the World Health Organization. "Our old drugs are becoming less and less effective as bacteria become more and more resistant to them," explains Gerry Wright, a professor in McMaster's Department of Biochemistry and Biomedical Sciences and a researcher at the university's Michael G. DeGroote Institute for Infectious Disease Research. "About 4.5 million people die every year due to antibiotic-resistant infections, and it's only getting worse." Wright and his team found that the new molecule, a lasso peptide, holds great promise as an early drug lead because it attacks bacteria in a way that's different from other antibiotics. Lariocidin binds directly to a bacterium's protein synthesis machinery in a completely new way, inhibiting its ability to grow and survive. This is a new molecule with a new mode of action. It's a big leap forward for us." Gerry Wright, Professor in McMaster's Department of Biochemistry and Biomedical Sciences Lariocidin is produced by a type of bacteria called Paenibacillus, which the researchers retrieved from a soil sample collected from a Hamilton backyard. The research team allowed the soil bacteria to grow in the lab for approximately one year - a method that helped reveal even the slow-growing species that could have otherwise been missed. One of these bacteria, Paenibacillus, was producing a new substance that had strong activity against other bacteria, including those typically resistant to antibiotics. "When we figured out how this new molecule kills other bacteria, it was a breakthrough moment," says Manoj Jangra, a postdoctoral fellow in Wright's lab. In addition to its unique mode of action and its activity against otherwise drug-resistant bacteria, the researchers are optimistic about lariocidin because it ticks a lot of the right boxes: it's not toxic to human cells, it's not susceptible to existing mechanisms of antibiotic resistance, and it also works well in an animal model of infection. Wright and his team are now laser-focused on finding ways to modify the molecule and produce it in quantities large enough to allow for clinical development. Wright says because this new molecule is produced by bacteria - and "bacteria aren't interested in making new drugs for us" - much time and resources are needed before lariocidin is ready for market. "The initial discovery - the big a-ha! moment - was astounding for us, but now the real hard work begins," Wright says. "We're now working on ripping this molecule apart and putting it back together again to make it a better drug candidate."

For millions of people, losing muscle isn't just about weakness; it's about losing independence. Whether caused by Duchenne muscular dystrophy, aging or other degenerative conditions, muscle loss can make everyday activities – like walking, climbing stairs or even standing up – a daily struggle. But a recent discovery from researchers at the University of Houston College of Pharmacy could help change that. The team, led by Ashok Kumar, Else and Philip Hargrove Endowed Professor of Drug Discovery and director of the Institute of Muscle Biology and Cachexia, discovered a potential therapeutic target in muscular disorders by identifying a previously unrecognized role of a protein called Fn14 in regulating satellite cell stability and function. They have published their findings in JCI Insight. Also known as muscle stem cells, satellite cells are responsible for muscle growth, repair and regeneration Our research highlights how Fn14 helps in preserving muscle stem cells and ensuring efficient muscle regeneration. By better understanding this mechanism, we can explore new ways to support muscle repair in conditions such as Duchenne muscular dystrophy and age-related muscle loss." Meiricris Tomaz da Silva, a post-doctoral fellow in Kumar's lab and the paper's first author Doctoral student Aniket S. Joshi was also on the team. The study demonstrated that the levels of Fn14 were increased in satellite cells after muscle injury. Conversely, reduction in satellite cell content and function is a significant contributor for skeletal muscle wasting in many conditions, including aging and degenerative muscle disorders, such as muscular dystrophy. "We have discovered the role of fibroblast growth factor–inducible 14 (Fn14) in the regulation of skeletal muscle regeneration in response to acute injury and in a model of Duchenne muscular dystrophy," reports Kumar. "The study shows that Fn14 is important for maintaining muscle stem cell pool in adult skeletal muscle." The results of Kumar's present and previous studies published in Life Science Alliance journal demonstrate that Fn14 signaling is crucial for muscle progenitor cells, which are early-stage cells that help form new muscle, to multiply and fuse with injured muscle fibers, promoting repair and regeneration. "Our findings suggest that augmenting the levels of Fn14 in satellite cells could be an important therapeutic approach for various muscle wasting conditions, such as aging and degenerative muscle disorders," said Kumar. "These findings deepen our understanding of muscle stem cells and could inform future strategies to enhance muscle regeneration in conditions involving chronic muscle loss."

Wearable mobile health technology could help people with Type 2 Diabetes (T2D) to stick to exercise regimes that help them to keep the condition under control, a new study reveals. Researchers studied the behaviour of recently-diagnosed T2D patients in Canada and the UK as they followed a home-based physical activity programme – some of whom wore a smartwatch paired with a health app on their smartphone. They discovered that MOTIVATE-T2D participants were more likely to start and maintain purposeful exercise at if they had the support of wearable technology- the study successfully recruited 125 participants with an 82% retention rate after 12 months. Publishing their findings in BMJ Open today (27 Mar), an international group of researchers reveal a range of potential clinical benefits among participants including improvements in blood sugar levels and systolic blood pressure. Our findings support the feasibility of the MOTIVATE-T2D intervention – paving the way for a full-scale randomized controlled trial to further investigate its clinical and cost-effectiveness. We found that using biometrics from wearable technologies offered great promise for encouraging people with newly diagnosed T2D to maintain a home-delivered, personalised exercise programme with all the associated health benefits." Dr. Katie Hesketh, Co-Author, University of Birmingham Researchers found that, as well as the encouraging data for blood sugar and systolic blood pressure, the programme could help to lower cholesterol and improve quality of life. The programme saw participants gradually increasing purposeful exercise of moderate-to-vigorous intensity – aiming for a target of 150 minutes per week by the end of 6 months and supported by an exercise specialist-led behavioural counselling service delivered virtually. MOTIVATE-T2D used biofeedback and data sharing to support the development of personalised physical activity programmes. Wearable technologies included a smartwatch, featuring a 3D accelerometer and optical heart rate monitor, synced with an online coaching platform for the exercise specialist and web/smartphone app for participants. "The programme offered a variety of workouts, including cardio and strength training, that could be done without the need for a gym," added Dr. Hesketh. "Its goal is to make exercise a sustainable part of daily life for people with Type 2 Diabetes, ultimately improving their physical and mental health." The feasibility trial recruited participants aged 40-75 years, diagnosed with T2D within the previous 5-24 months and managing their condition through lifestyle modification alone or Metformin.

Pediatric high-grade gliomas, particularly H3K27M diffuse midline gliomas (DMG), are aggressive malignant brain tumors with a poor prognosis. Previous research suggests that platelet-derived growth factor receptor alpha (PDGFRA) appears to play a multifaceted role in the pathogenesis of both adult and pediatric high-grade gliomas. Not only are genetic alterations of PDGFRA common in patients with pediatric high-grade gliomas, but elevated PDGFRA expression has been shown to be key in driving growth of DMG tumors. Now, findings of a recent multicenter study led by Mariella Filbin, MD, PhD, co-director of the Brain Tumor Center at Boston Children's Hospital and Dana-Farber Cancer Institute, suggest that PDGFRA could be a potential therapeutic target for pediatric high-grade gliomas. Filbin and her team - including collaborators at the University of Michigan Medical School and the Medical University of Vienna - also provide the first real-world clinical data to support the use of a PDGFRA inhibitor in the treatment of certain pediatric patients with high-grade gliomas. Pinpointing a potential treatment target To determine the frequency of PDGFRA alterations in pediatric high-grade gliomas, Filbin and her colleagues analyzed genomic data from 217 pediatric high-grade glioma samples. They identified PDGFRA alterations in nearly 15 percent of patients. Using transcriptomic data, they also found significantly elevated PDGFRA expression in tumors with PDGFRA mutation or amplification. Next, the team tested the activity of four PDGFRA inhibitors (dasatinib, crenolanib, axitinib, and avapritinib) against a panel of glioma cell lines with PDGFRA alterations. Of these drugs, avapritinib exhibited the highest potency. Additional pre-clinical testing found that avapritinib also had the least amount of off-target kinase activity, suggesting drug is less likely to cause unintended side effects. Promising early clinical data Finally, following additional testing in mouse models, the researchers treated eight pediatric and young adult patients who had high-grade gliomas with avapritinib through a compassionate use program. Most of the patients had DMGs, and seven of the eight had PDGFRA alterations. All had previously undergone surgical biopsy or resection and radiation, and four had also received chemotherapy or other treatment approaches. After being treated with avapritinib once daily for an average of four months, three of the patients demonstrated a radiographic response. The drug was also well tolerated. These three patients also survived roughly twice as long as those who didn't respond to avapritinib, although their disease ultimately metastasized. This early data suggests that avapritinib is generally safe and may trigger an initial clinical response in a small group of patients who have pediatric high-grade gliomas with PDGFRA amplification. Our research now provides the basis for a clinical trial for avapritinib in newly diagnosed pediatric patients. Our follow-up work focuses on genetic markers for personalized treatment and developing combination therapies with FDA-approved drugs to enhance efficacy." Mariella Filbin, MD, PhD, Co-Director of the Brain Tumor Center at Boston Children's Hospital and Dana-Farber Cancer Institute

Rut Besseling, Jan-Piet Wijgergangs, Michiel Hermes, Nick Koumakis, InProcess-LSP The Netherlands In downstream processing of biopharmaceutical products, protein aggregation presents one of the main risks in terms of therapeutic efficacy, safety and quality of these products. This study demonstrates monitoring of aggregation dynamics of BSA protein solutions during peristaltic pumping, with a single instrument (NanoFlowSizer) that measures both submicron and rare subvisible particles. The results show a near linear increase in both aggregate types with processing time. The unique dual-mode approach enables efficient, non-invasive quality control in protein downstream processing. Introduction Protein-based therapeutics have transformed treatments for numerous diseases, yet their production remains highly complex and cost-intensive [1][2],[3][4]. Downstream processing (DSP), including chromatography, ultra/diafiltration and fill-finish, often constitutes a major fraction of manufacturing expenses, and may account for more than half of total production costs. A central challenge in DSP is product stability, as biopharmaceutical proteins can be highly sensitive to environmental stresses, causing protein aggregation, reduced therapeutic efficacy and immunogenic risks. Among the various forms of protein aggregates, subvisible (~1–100 µm) and submicron (<1 µm) particles are of particular regulatory and clinical concern. Conventional methods for measuring them typically involve multiple techniques, e.g. Light Obscuration for subvisible particles (see e.g. USP<788>) or Dynamic Light Scattering (DLS) for submicron analysis. This creates logistical, economic, and practical challenges in process development or manufacturing settings. A unified approach that quantifies both subvisible and submicron particles with a single instrument provides a more streamlined and comprehensive assessment of product stability at various DSP stages, helping manufacturers mitigate aggregation during the most costly processing steps. This paper describes such an approach. An instrument providing in parallel advanced Spatially Resolved DLS and imaging (NanoFlowSizer) was employed to monitor protein aggregates of different sizes during a peristaltic circulation process. Such a monitoring strategy at critical downstream operations can help to illuminate where and how aggregation is triggered, keep control over Critical Quality Attributes, and support a more cost-effective, quality-focused DSP. The results underscore the value of advanced particle characterization tools in safeguarding therapeutic protein integrity while reducing resources and complexity of current workflows. Protein aggregation by mechanical stress and process impact Protein aggregation often arises from the partial unfolding of proteins, which exposes hydrophobic regions prone to self-association. While chemical factors like pH and temperature play key roles, mechanical stress and wall interactions—such as shear forces generated by pumping, stirring, or filtration—can also drive and accelerate aggregation5. Under high shear, proteins can undergo conformational changes, leading to clusters of misfolded molecules. Once formed, aggregates may continue to grow through secondary nucleation events, exacerbating the problem. From a manufacturing standpoint, protein aggregation can severely impact the most cost-intensive parts of downstream processing, reducing overall product yield and purity. Filtration membranes can become fouled by aggregates, reducing flow rates, increasing differential pressures, and necessitating frequent cleaning or replacements. Chromatography columns can lose efficiency when overloaded with aggregated material, elongating process times. These factors translates directly to higher labor, equipment, and material expenses. Moreover, stringent quality requirements in biopharmaceutical production underscore the need for aggregate-free products to mitigate e.g. immunogenicity risks. There are thus significant investments in strategies to detect and prevent aggregation, from buffer optimization and lowering shear through gentle mixing/transport protocols, to the use of specialized equipment designs, both for individual DSP steps and for their monitoring. Figure 1. A) Peristaltic loop for circulating BSA solution, including the NanoFlowSizer (NFS) with a ¼ inch flow cell. B) PhaSR measurements of DLS correlation functions of the BSA solution, after different circulation times. C) Snapshot of an LPD-movie, after 5hr circulation. Encircled particles have an estimated size1 > 1μm. The blue line marks the glass wall of the flow cell. Image Credit: InProcess-LSP Advanced Dynamic Light Scattering and Imaging combined The method of Spatially Resolved Dynamic Light Scattering—unique for the NanoFlowSizer (NFS) instruments (Fig.1A)—has established itself as a versatile technique for advanced, fast, and non-invasive size characterization of nanosuspensions.6,7,8,9,10 Two new measurement modes introduced in the NFS (PhaSR-DLS and LPD, see Fig. 1B and C) make the instrument particularly suited for characterizing biopharmaceuticals and protein aggregates over different size and concentration ranges: (i) PhaSR-DLS provides highly sensitive phase-resolved DLS data to measure both protein monomers and small concentrations of aggregates down to ~108 particles/ml.11 (ii) The ‘Large Particle Detection’ (LPD) mode enables rapid cross-sectional video imaging, allowing for the detection of rare large aggregates at concentrations as low as <104/ml.12 A snapshot of an LPD image sequence is shown in Fig. 1C. Monitoring protein aggregate formation by peristaltic pumping In this study, the NanoFlowSizer-Thalia2 instrument was integrated into a peristaltic pumping cycle2 in which a 5 mg/ml BSA suspension (in 0.1 M NaCl) was circulated at a relatively high flow rate of ~3.6 L/hour (see Figure 1A). This mimics situations that may occur in DSP process development, in which significant mechanical stresses during suspension transport can affect product stability and quality. Monitoring of the Particle Size Distribution (PSD) and the aggregation state of the suspension during extended peristaltic pumping was carried out using a cycle of 10 seconds of continuous pumping followed by a 25-second pause. During each pause, PhaSR-DLS and LPD measurements were taken and recorded in real time via the software. Although both PhaSR-DLS and LPD are compatible with continuous-flow measurements, the paused-flow method was chosen in this case (controlled via software) to ensure the highest quality PhaSR-DLS data for detecting submicron aggregates—without needing to limit the flow rate or use a larger NFS flow cell. Footnote: 1 A monotonous approximation, similar to that in [15], was employed for the backscattering intensity of protein aggregates. These aggregates are assumed here to have irregular shapes and a refractive index ~1.45. Note that the RI and standards for protein aggregate characterization is an active research field, see [16] 2 Using a Flexicon PF7 peristaltic pump and 1.2mm Accusil Platinum cured tubing. Total volume of BSA suspension: ~100ml. The mean wall shear rate in the tubing away from the peristaltic rollers is ∼5000 s^(-1). Submicron Aggregates The data in Figure 1B show PhaSR-DLS correlation functions after different circulation times. The two decay rates in the data clearly highlight the presence of the BSA ‘monomers’ (fast decay), along with a contribution from aggregates (slow decay). The latter starts at a residual level for the initially prepared solution (0 min) and increases on continued circulation. The intensity based PSDs from the PhaSR-DLS data, displayed in Figure 2A, shows that the aggregates have a hydrodynamic diameter ~150-400nm. The intensity fraction of this contribution systematically increases with process time, at the expense of the monomers. Figure 2. A) Particle Size distributions from PhaSR-DLS, at the timepoints in Fig.1B). Prolonged circulation causes an increasing intensity fraction of submicron aggregates. B) The resulting scattered intensity from submicron aggregates increases approximately linearly with circulation time. C) Snapshots of LPD image series after different circulation times (for clarity, an intensity threshold was chosen to show particles >800 nm in size). D) Concentration of ‘subvisible’ aggregates (size exceeding ∼1 μm) from LPD histograms, as function of processing time. After the first ∼100 minutes where pre-existing aggregates dominate, the aggregate concentration grows approximately linearly. Image Credit: InProcess-LSP As temperature was kept at ambient level and other factors were also constant, the aggregation is most likely due to the mechanical stresses from peristaltic pumping. Particularly in the “pinch” regions of the tubing where the rollers compress the fluid, such stresses can be strong, proteins may absorb on the tubing followed by desorption in the form of aggregates 5,13,14. For the submicron aggregates observed by PhaSR-DLS, scattering intensity estimates3 indicate that these aggregates contribute at most <0.1 vol% of the total protein. Footnote: 3 Based on Rayleigh approximation. For a more direct signature of the evolution of submicron aggregates, the intensity fraction from PhaSR-DLS can be combined with the total scattered intensity to analyse the scattered intensity only from submicron aggregates. The result is shown in Fig. 2B for the full >20hr course of the circulation run, indicating that the intensity from aggregates grows in proportion to the processing time. Subvisible Aggregates While the data in Fig. 2A,B do not clearly highlight aggregates larger than ~1 μm (labelled ‘subvisible’ here), such aggregates are in fact present, but at much lower levels, at which PhaSR-DLS (or standard DLS) cannot accurately measure them. Here the LPD imaging mode of the NFS instrument is well suited to resolve these ‘rare’ subvisible particles. In Fig. 2C, snapshots of LPD image series at different time points are shown (for clarity, a threshold was chosen to show aggregates >~800nm, see1), indicating the increase in concentration of these large aggregates over time. Using intensity histograms of the LPD image sequences at each time point 12, the increase in subvisible aggregates can be monitored simultaneously with the PhaSR-DLS data on submicron aggregates. The LPD results are shown in Fig. 2D. Starting from a small concentration, during circulation the concentration of subvisible aggregates grows approximately linear in time. Overall, the data in Fig. 2 strongly indicate that both submicron and subvisible aggregate concentrations are proportional to the time that the formulation is exposed to the mechanical stress. The significantly smaller fraction of subvisible particles (compared to submicron particles) is very hard or impossible to detect in standard DLS. Using the NFS with LPD uniquely provides the dual measurement capability shown in Fig. 2. Note that the contribution of subvisible particles to the total intensity is negligible, but they are nevertheless resolved in LPD. Submicron and subvisible particle measurements that usually require orthogonal (‘ensemble’ versus ‘single particle’) methods, can thus be characterized with the NanoFlowSizer instrument as a single non-invasive technique. Irreversible nature of the aggregates: mixture tests An aspect of protein aggregates often discussed in literature is their reversible or irreversible character. To assess this for the circulation run, the final aggregated suspension, after >20h of circulation, was mixed in vials with the starting suspension at different fractions. Using the NFS vial module, both PhaSR and LPD measurements were performed. The intensity from the submicron aggregates (via PhaSR-DLS) and the concentration of subvisible aggregates (from LPD) in the mixtures are shown in blue in Figure 3A and B, along with the results of the circulation run (black). The mixture data show that the concentration of both aggregate types changes -within measurement uncertainty- proportionally to the mixture fraction. The PSD data from PhaSR-DLS confirmed that the size of submicron particles was independent of mixture fraction. Thus, aggregates formed by peristaltic pumping are stable and only reduced in concentration when mixed with the original solution. The overlay with the peristaltic cycle data confirms the near linear increase of aggregate concentrations with time for the latter. Figure 3. A) Scatter intensity from submicron aggregates in the formulation and B) concentration of subvisible aggregates, as in Fig. 2B and D (versus time). The data are supplemented with the blue data of mixtures of the final aggregated solution and the original protein solution at different fractions of the aggregated solution, marked by ‘mixture fraction’. Image Credit: InProcess-LSP Lower concentration limits of LPD measurement Aggregate detection may be desired at levels significantly lower than discussed so far. As an example, in USP<787> for therapeutic proteins, particles ≥10μm may be present only at a level ≤25 particles /ml in the final product. As mentioned, PhaSR-DLS (or standard DLS) is unable to reliably measure at these levels. To assess detection levels of LPD under the employed conditions (<20s acquisition), two additional series of protein samples were prepared over 4 decades in concentration: (i) ‘Mixtures’ of a strongly aggregated BSA solution with a fresh BSA solution with residual aggregates and (ii) ‘Dilutions’ of the same aggregated BSA solution using filtered water. In Fig.4 the aggregate concentration (using a somewhat smaller threshold intensity corresponding to ~750nm particles) for the ‘Mixtures’ is shown in blue. It is proportional to the mixture fraction for fractions >0.02, while at lower fractions, a plateau occurs indicating the residual aggregate concentration. In contrast, for the ‘Dilutions’ of the aggregated solution with filtered water, the aggregate concentration is proportional to dilution down to <10^3 particles/ml. This highlights the complementary character of LPD and PhaSR: the latter provides high-sensitivity DLS data, the former provides very low concentration capabilities usually only offered by ‘single particle’ techniques.4 Footnote: 4 Note that also for well-established single particle techniques, measurements of subvisible particles may be significantly biased due to presence of submicron or ‘sub-countable’ particles 17 Figure 4. Aggregate concentrations for a strongly aggregated BSA solution, mixed in different fractions with a BSA solution with residual aggregates (blue data) or diluted with filtered water (black data). The mixture fraction or dilution factor extend over almost 4 decades to illustrate limits. Concentrations correspond to aggregates exceeding an estimated size of ~750nm. Image Credit: InProcess-LS Conclusion In summary, the unique combination of PhaSR-DLS and LPD in the NanoFlowSizer effectively tracks both submicron and rare subvisible protein aggregates, formed here during peristaltic pumping. These complementary data -usually requiring multiple instruments- facilitate protein downstream processing development and understanding the aggregation state of protein formulations. A near linear increase in aggregate concentration of both types is seen on extended circulation, underscoring the impact of mechanical stress on protein stability. The integrated, non-invasive measurement employed here provides real-time process insights, helping to detect and mitigate aggregation risks. The method can advance protein DSP by reducing complexity, costs, and boosting efficiency, while safeguarding product quality. Acknowledgments Produced from materials originally authored by Rut Besseling, Jan-Piet Wijgergangs, and Nick Koumakis from InProcess-LSP in The Netherlands. References W. Wang, “Protein aggregation and its inhibition in biopharmaceutics,” Int J Pharm, vol. 289, no. 1–2, pp. 1–30, Jan. 2005, doi: 10.1016/J.IJPHARM.2004.11.014. H. C. Mahler, W. Friess, U. Grauschopf, and S. Kiese, “Protein aggregation: Pathways, induction factors and analysis,” J Pharm Sci, vol. 98, no. 9, pp. 2909–2934, Sep. 2009, doi: 10.1002/JPS.21566/ASSET/66182FB5-76C5-42CD-BA73-36C76AF2BE9F/MAIN.ASSETS/GR2.JPG. C. J. Roberts, “Protein aggregation and its impact on product quality,” Curr Opin Biotechnol, vol. 30, pp. 211–217, Dec. 2014, doi: 10.1016/J.COPBIO.2014.08.001. N. B. Pham and W. S. Meng, “Protein aggregation and immunogenicity of biotherapeutics,” Int J Pharm, vol. 585, p. 119523, Jul. 2020, doi: 10.1016/J.IJPHARM.2020.119523. N. Deiringer and W. Friess, “Proteins on the Rack: Mechanistic Studies on Protein Particle Formation During Peristaltic Pumping,” J Pharm Sci, vol. 111, no. 5, pp. 1370–1378, May 2022, doi: 10.1016/J.XPHS.2022.01.035. R. Matthessen, R. Van Pottelberge, B. Goffin, and G. De Winter, “Impact of mixing and shaking on mRNA-LNP drug product quality characteristics,” Scientific Reports 2024 14:1, vol. 14, no. 1, pp. 1–11, Aug. 2024, doi: 10.1038/s41598-024-70680-4. T. Rooimans et al., “Development of a compounded propofol nanoemulsion using multiple non-invasive process analytical technologies,” Int J Pharm, vol. 640, p. 122960, Jun. 2023, doi: 10.1016/J.IJPHARM.2023.122960. R. Besseling and et al., “Real-Time Droplet Size Monitoring of Nano Emulsions During High Pressure Homogenization,” 2021. doi: 10.13140/RG.2.2.30640.28166. M. Sheybanifard et al., “Liposome manufacturing under continuous flow conditions: towards a fully integrated set-up with in-line control of critical quality attributes,” Lab Chip, vol. 23, no. 1, pp. 182–194, Dec. 2022, doi: 10.1039/D2LC00463A. L. Royer and et al., “Non-Invasive Particle Size Monitoring of Polymer-Based Vectors for Cell Transfection in Process Vessels,” https://www.news-medical.net/whitepaper/20250224/Non-Invasive-Particle-Size-Monitoring-of-Polymer-Based-Vectors-for-Cell-Transfection-in-Process-Vessels.aspx. N. ; H. M. W. Y. W. J.-P. S. C. B. R. Koumakis, “‘PhaSR-DLS’: a new advancement in Spatially Resolved DLS for enhanced inline and off-line nanoparticle sizing,” https://www.azonano.com/article.aspx?ArticleID=6749. Accessed: Sep. 24, 2024. [Online]. Available: https://www.azonano.com/article.aspx?ArticleID=6749 M. Hermes and et al., “A new method for non-invasive or inline detection of aggregates and oversized particles in nanosuspensions.” Accessed: Mar. 22, 2025. [Online]. Available: https://www.news-medical.net/whitepaper/20241106/A-new-method-for-non-invasive-or-inline-detection-of-aggregates-and-oversized-particles-in-nanosuspensions.aspx T. B. Fanthom, C. Wilson, D. Gruber, and D. G. Bracewell, “Solid-Solid Interfacial Contact of Tubing Walls Drives Therapeutic Protein Aggregation During Peristaltic Pumping,” J Pharm Sci, vol. 112, no. 12, pp. 3022–3034, Dec. 2023, doi: 10.1016/J.XPHS.2023.08.012. T. B. Fanthom, “Mechanisms of Therapeutic Protein Aggregation During Peristaltic Pumping,” 2023. C. M. Sorensen, “Q-space analysis of scattering by particles: A review,” J Quant Spectrosc Radiat Transf, vol. 131, pp. 3–12, Dec. 2013, doi: 10.1016/J.JQSRT.2012.12.029. D. C. Ripple, M. J. Carrier, and J. R. Wayment, “Standards for the Optical Detection of Protein Particulates,” 2012. Accessed: Sep. 23, 2024. [Online]. Available: https://www.nist.gov/publications/standards-optical-detection-protein-particulates B. Tolla and D. Boldridge, “Distortion of Single-Particle Optical Sensing (SPOS) Particle Count by Sub-Countable Particles,” Particle & Particle Systems Characterization, vol. 27, no. 1–2, pp. 21–31, Dec. 2010, doi: 10.1002/PPSC.200900081. Footnotes 1A monotonous approximation, similar to that in C. M. Sorensen's study,14 was employed for the backscattering intensity of protein aggregates. These aggregates are assumed here to have irregular shapes and a refractive index ~1.45. Note that the RI and standards for protein aggregate characterization is an active research field.15 2 Using a Flexicon PF7 peristaltic pump and 1.2mm Accusil Platinum cured tubing. Total volume of BSA suspension: ~100ml. The mean wall shear rate in the tubing away from the peristaltic rollers is ∼5000 s-1. 3 Based on Rayleigh approximation. 4Note that also for long-established single particle techniques, measurements of subvisible particles may be significantly biased due to presence of submicron or ‘sub countable’ particles.16 About InProcess-LSP InProcess-LSP, headquartered in Oss at Pivot Park, is a rapidly growing, innovative company founded in 2014. Backed by a team of in-house experts—comprising physicists, chemists, and software engineers—InProcess-LSP is at the forefront of nanotechnology solutions. The company’s leading product, the NanoFlowSizer, is a cutting-edge instrument designed to deliver inline, real-time measurements of nanoparticles in solution, making it indispensable across various industries. Utilizing Spatially Resolved Dynamic Light Scattering (SR-DLS) technology, the NanoFlowSizer enables accurate characterization of nanoparticles in flowing liquids, providing critical data such as hydrodynamic diameter, polydispersity index (PDI), and D90 within seconds. This state-of-the-art instrument empowers both scientists and industries by offering a robust solution for analyzing nanoparticle properties, paving the way for breakthroughs in product development, improved formulations, and pioneering applications. Innovators in Process Analytical Technology and nanoparticle characterization. With their strong background in process analytics as well as many years of academic and industrial experience InProcess offer a highly skilled and experienced team of scientists and process specialists addressing the needs of your PAT and nanotechnology challenges. Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.

The Chan Zuckerberg Initiative (CZI) announced a new grand challenge to develop groundbreaking imaging technologies to transform how scientists observe, measure and understand living cells and organisms. CZI's two powerhouse institutes, CZ Biohub San Francisco and CZ Institute for Advanced Biological Imaging, will leverage their complementary expertise to form a new Biohub unmatched in the field of life science imaging research. They will combine their teams at a new science campus in Redwood City, Calif., adjacent to CZI headquarters. These institutes are leveraging their complementary strengths at a critical moment in biological discovery - when the right combination of technological and scientific expertise can create novel tools to illuminate hidden dynamics of complex systems, like the brain and immune system, to fully understand how they function." Priscilla Chan, co-founder and co-CEO of CZI Scott Fraser, CZI's vice president of science grant programs, has accepted the role of president of the Chan Zuckerberg Imaging Institute effective April 1. He will lead the new grand challenge and work with the CZ Imaging Institute, CZ Biohub San Francisco and CZI leaders to lay the groundwork for the two institutes to form a new Biohub, which will join existing institutes in the CZ Biohub Network. Dr. Fraser is renowned for innovative work in biological imaging as a professor of biological sciences and biomedical engineering. His achievements include developing techniques to visualize biological processes in living organisms, advancing 4D imaging for embryonic development, and creating methods to track cells and molecules. Building on the successful Biohub model The San Francisco Biohub was one of CZI's first big bets in science, including CZI's powerful model for enabling research that brings different disciplines together to tackle large scientific challenges. At the San Francisco Biohub, scientists and engineers are developing cutting-edge tools that advance understanding of dynamic cell systems across scales in healthy and diseased states. Their work has resulted in a first-of-its-kind complete map of zebrafish embryo development and a first-draft human cell atlas of over 1.1 million cells. The success of the Biohub's collaborative model inspired the approach of two other Biohubs in Chicago and New York, as well as the Chan Zuckerberg Imaging Institute, which is focused on building novel imaging technologies and visualization tools to reveal the inner workings of cells and cell systems. Working closely with the bioimaging community, the CZ Imaging Institute has already sped the cryo-ET pipeline by almost 100-fold, and addresses critical research challenges through initiatives like the cryo-ET data portal and an ML challenge designed to automate molecular labeling in 3D cellular images-directly tackling a major bottleneck in in-situ structural biology research. Illuminating the dynamic architecture of living systems The vision for the new Biohub is to develop novel imaging systems to illuminate the dynamic architecture of living systems, making what was invisible visible, measurable and understandable. Living systems are in constant motion, with cells, tissues and organs continuously changing in complex and interconnected ways. Current imaging technologies provide only static snapshots or limited views of these dynamic processes, leaving scientists and physicians with an incomplete understanding of how biological systems function, and what goes wrong in disease. To change this, the combined teams will develop breakthrough imaging technologies integrated with molecular analysis methods that can capture biological processes across multiple scales-from individual proteins to whole organisms. These new capabilities will validate virtual cell models, guide cell engineering strategies, and reveal organizing principles for tissue engineering. "Leading a grand challenge and a research institute of this magnitude is an honor," said Scott Fraser, incoming president of the Chan Zuckerberg Imaging Institute. "By fusing the San Francisco Biohub and the Imaging Institute together, both leaders in their respective fields, we will have the ability to revolutionize how scientists explore, understand and ultimately harness the fundamental processes of life. This is an exciting time for science and for CZI." To support this transformative research, the unified Biohub will be based in Redwood City in 2027, creating a new science campus at Elco Yards, currently under construction. This campus will foster collaboration across disciplines-bringing together a world-class team of scientists, engineers, and artificial intelligence and machine learning experts-to build novel tools and technologies that will make new discoveries possible and accelerate progress toward curing, preventing or managing diseases in this century. "Since its inception, the Chan Zuckerberg Initiative has made bold, long-term investments in scientific research and technology to advance understanding of human biology," said Joe DeRisi, president of the CZ Biohub San Francisco. "Having the San Francisco Biohub and the Imaging Institute join together for this grand challenge is a natural fit and is an example of CZI continuing to make big bets in science. I look forward to working with Scott Fraser and our colleagues over the next two years on this exciting work." The San Francisco Biohub launched in 2016 with a 10-year commitment to address some of the most important questions in science. Joe DeRisi will continue to lead the organization through its initial commitment and support the evolution of its work as it joins with the Chan Zuckerberg Imaging Institute.

New research reveals how plant-based flavonoids can regulate gut hormones like GLP-1 and ghrelin, offering a natural strategy to manage insulin resistance and slow the progression of type 2 diabetes. Study: The Emerging Role of Flavonoids in the Treatment of Type 2 Diabetes Mellitus: Regulating the Enteroendocrine System. Image Credit: Shutterstock AI Generator / Shutterstock.com A recent review published in the journal Exploratory Research and Hypothesis in Medicine discusses flavonoids' role in regulating the enteroendocrine system and their potential efficacy in treating type 2 diabetes mellitus (T2DM). What are flavonoids? Flavonoids are plant-based substances found throughout nature associated with numerous health benefits. Over 10,000 different flavonoid compounds have been identified, most of which can be categorized as flavonols, anthocyanidins, flavonones, flavonols, isoflavones, flavones, and chalcones. Several studies have described the antioxidant, anti-inflammatory, lipid-regulating, cytotoxic, antibacterial, and anticancer properties associated with flavonoid compounds. More recently, researchers have reported that flavonoids may also exhibit anti-diabetic effects through various mechanisms. The impact of flavonoids on insulin sensitivity and oxidative stress Insulin resistance (IR) arises when muscle, fat, and liver cells become less sensitive to the activity of insulin, which can prevent efficient uptake and storage of glucose. Several studies have reported that certain flavonoids may improve insulin sensitivity through different mechanisms. For example, cyanidin-3-O-glucoside has been shown to suppress protein tyrosine phosphatase 1B levels, thereby increasing phosphorylation of insulin receptor substate 2 (IRS-2). Cyanidin-3-O-glucoside also appears to inhibit IRS-1 phosphorylation, which reduces tumor necrosis factor α (TNF- α),-induced insulin resistance in adipocytes. Oxidative stress occurs when an imbalance exists between the production of reactive oxygen species (ROS) and antioxidant intracellular activities. During T2DM, mitochondrial dysfunction can increase ROS generation, thereby leading to IR, vascular complications, and β-cell damage in the pancreas to prevent sufficient insulin production. Flavonoids such as naringin and fucoidan can reduce ROS levels by increasing mitochondrial membrane protection and protecting β-cells against inflammation, respectively. Flavonoids, the enteroendocrine system, and T2DM management T2DM has a wide range of adverse effects on various enteroendocrine cells (EECs), crucial for maintaining metabolic homeostasis. For example, several studies have reported that T2DM reduces the effectiveness of the incretin hormone and density of cells responsible for secreting glucagon-like peptide 1 (GLP-1). The effects of flavonoids on the enteroendocrine system have been widely reported. Chlorogenic acid and curcumin, both phenol compounds, have been shown to increase GLP-1 levels in humans and mice, respectively. Multiple studies confirm that flavonoids regulate GLP-1, auxin-releasing peptide, peptide YY (PYY), and cholecystokinin (CCK).” Grape seed proanthocyanidin extract (GSPE) can also reverse the decline of GLP-1 messenger ribonucleic acid (mRNA) levels in the colon. Hispidulin, a flavonoid isolated from medicinal plants, also facilitates GLP-1 release by stimulating L cells, further enhancing blood glucose control. Glucose-dependent insulinotropic polypeptide (GIP) stimulates the secretion of glucagon under lower plasma glucose concentrations, thereby aiding glycemic management. Although research suggests that flavonoids may promote insulin secretion by inhibiting glucagon secretion in T2DM, thereby preserving GIP levels, these observations have not been confirmed by larger studies. CCK is produced by I cells in the duodenum. Flavonoids, such as quercetin, kaempferol, apigenin, rutin, and baicalein, may regulate blood sugar levels and food intake by influencing CCK secretion. Flavonoids may influence blood glucose levels in T2DM patients by altering somatostatin secretion, which can subsequently impact the secretion of CCK. Catechins may inhibit somatostatin release by decreasing gastrin secretion in G cells; however, the mechanisms involved in this activity remain unclear. Serotonin suppresses appetite in mammals, regulates fluid secretion, intestinal motility, and vasodilation, in addition to promoting insulin secretion in the pancreas. Supplementation with quercetin has been shown to improve serotonergic function impaired by diabetes. Likewise, an extract of the Viscum album plant was reported to increase elevated serotonin levels, whereas luteolin decreased fat degradation in Caenorhabditis elegans, more commonly referred to as roundworm. Plasma levels of ghrelin, a hormone that stimulates appetite and enhances food intake, rise during fasting and decrease after meals. In T2DM patients, reduced plasma ghrelin activity has been significantly associated with IR and hyperinsulinism. In rat anterior pituitary cells, quercetin 3-O-malonylglucoside (Q3MG), obtained from mulberry leaves, has been shown to augment ghrelin secretion. Phloretin supplementation also led to a significant rise in ghrelin in C57BL/6J mice. Conclusions Flavonoids have the potential to control T2DM by regulating gut hormones; therefore, supplementation with beneficial flavonoids may delay T2DM progression and/or assist in the management of this disease. However, the precise molecular pathways by which flavonoids influence intestinal hormones remain unclear, thus highlighting the need for larger, long-term studies to translate these findings into clinical practice.

Cabozantinib, an oral tyrosine kinase inhibitor, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with previously treated advanced neuroendocrine tumors (NETs). This represents a new standard of care therapy for this patient population. The FDA approval was based on results from the CABINET study, a phase 3 pivotal trial evaluating cabozantinib compared with placebo in two groups of patients with previously treated NETs: advanced pancreatic NETs and advanced extra-pancreatic NETs. The study was led by Jennifer Chan, MD, MPH, clinical director of the gastrointestinal cancer center and director of the program in carcinoid and neuroendocrine tumors at Dana-Farber Cancer Institute. Patients with neuroendocrine tumors often face a difficult journey. Despite advances in recent years, there has remained a critical need for new and effective therapies for patients whose cancer has grown or spread. Cabozantinib significantly improved outcomes in this patient population and this FDA approval provides new hope." Jennifer Chan, MD, MPH, clinical director of the gastrointestinal cancer center and director of the program in carcinoid and neuroendocrine tumors at Dana-Farber Cancer Institute Cabozantinib works by targeting multiple pathways involved in tumor growth and angiogenesis. Patients with NETs treated with the drug survived significantly longer with no worsening of their disease compared to patients who received a placebo. Side effects of cabozantinib were like those found in other studies of the drug. These include hypertension, fatigue, and diarrhea. Final progression-free survival results were presented at the 2024 European Society for Medical Oncology Congress and published in The New England Journal of Medicine. Based on improved efficacy at interim analysis, the trial was stopped early and unblinded in August 2023. More than 12,000 people in the United States are diagnosed with a NET each year. The tumors begin in neuroendocrine cells – which have characteristics of nerve and hormone-producing cells – and can arise in multiple sites in the body, most often in the gastrointestinal tract, lungs, and pancreas. The number of people diagnosed with NETs has been increasing in recent decades. Treatments may include surgery, molecular targeted therapy, peptide receptor radionuclide therapy, chemotherapy, or other local treatment approaches depending on the location and stage of the cancer. For patients whose cancer continues to grow and spread after these treatments, better options are urgently needed. The CABINET trial was sponsored by the NCI, part of the National Institutes of Health (U10CA180821, U10CA180882), and was led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCTN as part of Exelixis' collaboration with the NCI's Cancer Therapy Evaluation Program (NCI-CTEP); https://acknowledgments.alliancefound.org.

A small molecule shaped like a lasso may be a powerful tool in the fight against infectious diseases, according to a new study in Nature co-authored by University of Illinois Chicago researchers. Lariocidin, a peptide made by bacteria living in soil, was effective against several different microbes responsible for deadly infections. UIC researchers working with collaborators at McMaster University in Canada determined how the new antibiotic works and why the drug evades bacterial resistance. The holy grail in the field is to find an antibiotic that binds to a new site target, has a novel mechanism of action and has a new structure, compared to antibiotics that have been known before. Lariocidin hits all these goals." Alexander Mankin, distinguished professor of pharmaceutical sciences at UIC The paper was co-authored by UIC postdoctoral researcher Dmitrii Travin and includes UIC co-authors Mankin, Elena Aleksandrova, Dorota Klepacki, Nora Vázquez-Laslop and Yury Polikanov. Lariocidin is a newly discovered member of the lasso peptide family – tiny proteins shaped like a lasso, with a loop of amino acids at one end and a tail threaded through it. The new peptide was discovered in bacteria collected in the backyard of one of the scientists in Canada. After McMaster researchers observed that lariocidin could kill several disease-causing microbes, they worked with the UIC researchers to study how it works. In biochemical and structural experiments, the team found that lariocidin binds to and blocks the ribosome, the cell's factory for making new proteins. "We found a new job for these lasso peptides," Travin said. "No one knew that lasso peptides could bind to the ribosome and kill bacteria by not allowing them to make new proteins." Because lariocidin binds at a site different from where other antibiotics bind to ribosomes, it avoids the defenses that bacteria have evolved to resist other drugs. "In the antibiotic discovery field, you want a weapon which kills by targeting something different than the previous ones did before," said Polikanov, associate professor of biological sciences. "Otherwise, previously used protections will automatically lead to defense against the new molecule." The peptide's unique structure may also help circumvent another common bacterial defense, Travin said. To tie up a ribosome, an antibiotic first needs to get inside the bacterial cell. Many drugs sneak in through transporters, but bacteria can change or remove these to block the drugs. By contrast, lariocidin has a strong positive charge, which likely allows it to pass directly through membranes without the need of transporters. That makes the molecule a broad-spectrum antibiotic. "If you do not rely on any specific transporter, you can penetrate the majority of bacteria," Travin said. "And if a transporter is not needed, then the probability of resistance is lower." The researchers additionally studied a variant of lariocidin, which takes on a more intricate three-dimensional shape, looping its tail to resemble a pretzel. This even more stable structure might be the most promising candidate for clinical development, the researchers said. The bioinformatic analysis of available bacterial genomes suggests there could be other lasso and pretzel peptides that target ribosomes still to be discovered in nature. "Essentially, lariocidin is the founding member of a new family of antibiotics with a similar mechanism of action," Travin said. "Time will show whether some other peptides of this kind will be even more active than this one. But we already have our foot in the door." Funding for the research was provided by National Institutes of Health to Polikanov, Mankin and Vázquez-Laslop.

Researchers from the J. Craig Venter Institute (JCVI), the Friedrich-Loeffler-Institut (FLI), and the International Livestock Research Institute (ILRI) have developed a reverse genetics system for African swine fever virus (ASFV). This new system will aid researchers in developing vaccines and in studying the pathogenesis and biology of ASFV, a highly contagious, deadly viral disease affecting domesticated and wild pigs, especially prevalent in Africa, Europe, Asia, and the Caribbean. A recent study estimates if ASFV reached the United States it could result in economic losses exceeding $50 billion over a ten-year period. By developing a synthetic genomics-based reverse genetics system for ASFV, we are not only advancing our understanding of this virus but also creating tools that can be applied to other emerging viral threats. This research has the potential to significantly reduce the economic losses caused by ASFV in the global swine industry, providing much-needed solutions to control and prevent the spread of the disease." Sanjay Vashee, Ph.D., senior author on the paper, JCVI Professor The reverse genetic system allows scientists to quickly generate genetically modified versions of ASFV and involves several steps. First, scientists construct synthetic DNA, which is a lab-made version of the virus's genetic material. Fragments of ASFV are modified and then assembled into full-length genomes in yeast using its recombination machinery. The modified genomes are then transferred to E. coli which makes isolating them in larger amounts possible. The synthetic DNA is then transfected (or artificially introduced) into mammalian host cells which are subsequently infected with a self-helper virus. This self-helper virus is an inhibited version of ASFV which has been modified using CRISPR/Cas9 technology, a powerful gene-editing tool that can precisely cut DNA at specific locations. The alterations ensure that the self-helper virus cannot replicate on its own. Despite this inhibition, the self-helper virus still provides the necessary proteins and machinery required for the synthetic DNA to replicate and assemble into new virus particles. This process results in the production of live recombinant viruses that contain the specific genetic modifications introduced in the synthetic DNA. These recombinant viruses can then be used for further study or vaccine development. "Globally, ASF outbreaks have caused devastating economic losses amounting to billions of dollars, severely impacting the pork industry, food security, and livelihoods. In Africa, the impact could be dire given the presence of multiple genotypes of the virus and the widespread lack of adequate biosecurity measures to control the disease," said Dr. Hussein Abkallo, a researcher at ILRI and one of the authors of the paper. "This platform gives hope of developing new, targeted vaccines that can protect animal health to reduce mortality as well as the environmental footprint of the livestock sector by preventing unnecessary losses." The synthetic genomics-based reverse genetics system developed for ASFV can be applied to other viruses with non-infectious genomes, offering significant potential for research and vaccine development. For example, it could be applied to lumpy skin disease virus, a double-stranded DNA virus that primarily affects cattle causing significant economic harm. This methodology could also be adapted for emerging RNA viruses such as Zika, chikungunya, Mayaro, and Ebola viruses, which have caused significant outbreaks and pose serious threats to global health. By leveraging synthetic genomics, researchers can rapidly develop reverse genetics tools for these and new emerging viruses, facilitating the study of their biology and the creation of effective vaccines and treatments. In addition to Dr. Vashee, the study team included senior author Lucilla Steinaa, Ph.D. (ILRI) and first authors Walter Fuchs, Dr. rer. nat. (FLI) and Nacyra Assad-Garcia (JCVI). The complete study, "A synthetic genomics-based African swine fever virus engineering platform," may be found in the journal Science Advances. Funding for this work was provided by the International Development Research Centre (IDRC) Livestock Vaccine Innovation Fund (LVIF), phase I 108514 and phase II 109212.