A groundbreaking clinical trial is underway at Leicester, spearheaded by leading researchers aiming to revolutionize treatment options for patients afflicted with mesothelioma, a particularly rare yet aggressive form of cancer. This innovative research offers a glimmer of hope to those affected, potentially extending their survival and enhancing quality of life by tailoring therapies to individual genetic profiles.

Mesothelioma arises predominantly in the linings of the lungs or abdomen and is intimately connected to asbestos exposure, a factor that has rendered this malignancy notoriously difficult to treat. Despite approximately 2,700 new diagnoses annually in the UK, prognosis remains grim, with survival rates and available treatment strategies offering limited success. Traditional therapies fail to adequately address the biological heterogeneity of this cancer, underscoring the urgent need for novel, personalized interventions.

Central to this trial, known as SELECTmeso1, is the use of targeted cancer therapies designed to exploit specific genetic vulnerabilities within tumor cells. This approach addresses the problem of variable treatment efficacy by stratifying patients based on identifiable genetic biomarkers, thus aligning therapeutic strategies with the molecular underpinnings of each patient’s disease. Trials like SELECTmeso1 embody the forefront of precision oncology, promising more effective and less toxic interventions.

The project is a collaboration between esteemed institutions including the NIHR Biomedical Research Centres in Leicester and Southampton, with the Southampton Clinical Trials Unit managing operations and oversight. Backed financially by Asthma + Lung UK, this research initiative emphasizes the growing recognition within the medical community of the importance of precision medicine in oncology, especially for diseases with limited therapeutic options like mesothelioma.

Professor Dean Fennell, Chair of Thoracic Medical Oncology at the University of Leicester and lead investigator, highlights the crux of the personalized treatment paradigm: understanding the cancer’s unique genetic landscape. Nearly 50% of mesothelioma patients exhibit a deletion of the MTAP gene, a genetic anomaly that is intricately linked with more aggressive tumor behavior and resistance to conventional therapies. This genetic deletion simultaneously presents a distinctive therapeutic target.

The trial focuses on exploiting the absence of the MTAP gene to disrupt the cancer cells’ growth machinery selectively. In healthy cells, the MTAP gene is involved in critical metabolic pathways, but its deletion in cancer cells creates a biochemical dependency that can be targeted pharmacologically. The investigational drug, Navlimetostat (also referenced as BMS-986504), developed by pharmaceutical giant Bristol Myers Squibb, is a first-in-class PRMT5 inhibitor designed to exploit this metabolic vulnerability, thereby selectively inducing cancer cell death while sparing healthy tissue.

Navlimetostat operates by inhibiting protein arginine methyltransferase 5 (PRMT5), an enzyme crucial to the survival of cancer cells deficient in MTAP. By blocking PRMT5, Navlimetostat disrupts methylation-dependent processes vital to tumor cell proliferation and survival, effectively ‘starving’ the cancer at a molecular level. Early phase studies in other malignancies have shown promising anti-tumor activity and manageable safety profiles, laying a robust foundation for its evaluation in mesothelioma.

The SELECTmeso1 phase of the trial recruits patients with relapsed mesothelioma who test positive for the MTAP gene deletion. The trial administers Navlimetostat orally in three-week cycles, continuing up to six months. Researchers monitor both tumor response and patient tolerance meticulously, aiming to affirm the drug’s efficacy and safety within this highly specific patient subgroup.

This trial represents the initial stage of a larger adaptive platform study intending to evaluate multiple targeted agents against various genetic biomarkers across the spectrum of mesothelioma cases. By adopting a platform model, SELECTmeso aims to streamline clinical investigation, allowing simultaneous testing of several therapeutic candidates tailored to genetic signatures in patients’ tumors, thereby accelerating the pace of discovery and clinical translation.

Looking to the future, the platform design will incorporate molecular profiling of tumor samples to guide patient enrollment across sub-trials, each exploring a drug matched to a distinct biomarker. Such precision trials could transform the clinical landscape, enabling oncologists to offer bespoke therapies with improved outcomes versus the current ‘one-size-fits-all’ approach. Through this strategy, SELECTmeso1 pioneers a new chapter in mesothelioma treatment.

Dr. Samantha Walker of Asthma + Lung UK emphasizes the transformative potential of this research, especially given the dismal survival statistics and lack of curative options for mesothelioma patients. The advancement of targeted therapies has altered the natural history of multiple cancers, and the hope is that SELECTmeso1 will similarly deliver breakthroughs for this challenging disease, ultimately informing standard clinical practice worldwide.

The trial has already commenced recruitment at Leicester Royal Infirmary and will expand to ten additional UK hospitals, enrolling up to 30 patients for this initial evaluation. If successful, this could lay the groundwork for larger, practice-changing trials and establish a template for personalized cancer treatment paradigms not only for mesothelioma but also for other malignancies characterized by genetic heterogeneity.

In sum, the SELECTmeso1 trial exemplifies the cutting-edge intersection of genomics and oncology, demonstrating how understanding cancer’s molecular vulnerabilities can inform smarter, targeted treatments. It embodies the hope and progress achievable through collaborative research, innovative drug design, and precision medicine to improve survival and quality of life for patients facing devastating diagnoses.

Subject of Research: People

Article Title: Personalized Targeted Therapy Trial for Mesothelioma Opens New Frontiers in Cancer Treatment

News Publication Date: Not explicitly stated in source content

Web References:

• Leicester Biomedical Research Centre
• SCTU website
• Asthma + Lung UK
• MiST Trial Article
• CONFIRM Trial News
• NERO Trial News

References:
Cancer Research UK statistics on mesothelioma incidence and survival
Details of Navlimetostat (BMS-986504) as a first-in-class PRMT5 inhibitor by Bristol Myers Squibb

Image Credits: University of Leicester

Keywords: Mesothelioma, Targeted therapy, Personalized medicine, MTAP gene deletion, Navlimetostat, PRMT5 inhibitor, Clinical trial, Cancer research, Genetic biomarkers, Precision oncology, Cancer treatment, Drug development

In the delicate realm of neonatal intensive care, managing infants suffering from hypoxic-ischemic encephalopathy (HIE) presents a multifaceted challenge. Therapeutic hypothermia (TH) has emerged as the cornerstone treatment for neonatal encephalopathy, significantly improving neurological outcomes by mitigating ongoing brain injury that occurs after asphyxia at birth. However, the sedation and analgesia required during TH add complexity to clinical care. Traditionally, morphine has been the analgesic agent of choice, but concerns over its respiratory depressant effects and potential neurodevelopmental consequences have prompted the search for safer alternatives. Enter dexmedetomidine, a potent alpha-2 adrenergic receptor agonist known for its sedative and analgesic properties without significant respiratory compromise. Yet, despite its promising pharmacological profile, the safety and pharmacokinetics (PK) of dexmedetomidine in neonates undergoing cooling therapy remain largely unexplored—until now.

A groundbreaking clinical trial, aptly named the DICE trial (Dexmedetomidine use in Infants undergoing Cooling due to neonatal Encephalopathy), spearheaded by Baserga et al., has cast new light on this issue. Published recently in Pediatric Research, the trial meticulously investigates both the safety parameters and PK behavior of dexmedetomidine when administered to cooled neonates. This research addresses a critical void in pediatric pharmacology, potentially reshaping sedation practices in neonatal intensive care units worldwide.

Therapeutic hypothermia involves lowering the infant’s core temperature to 33.5°C for 72 hours, slowing metabolic processes and reducing neuronal damage after birth asphyxia. While TH improves survival and reduces disability rates, it also complicates drug metabolism due to the altered physiologic state induced by hypothermia. Infants undergoing TH frequently require continuous sedation to prevent shivering and alleviate stress, conditions that exacerbate brain injury if unmanaged. The sedative agent must provide effective analgesia without impeding vital respiratory functions or prolonging recovery. Morphine, despite being widely utilized, is not an optimal candidate due to dose-dependent respiratory depression and a potentially detrimental impact on developing neural circuits.

Dexmedetomidine’s mechanism of action involves selective stimulation of alpha-2 adrenergic receptors in the locus coeruleus region of the brainstem, leading to decreased norepinephrine release and hence sedation and analgesia. Unlike opioids, it typically does not cause respiratory depression, making it an attractive alternative for fragile neonates on TH. However, neonates present unique challenges due to immature hepatic enzyme systems and renal functions, making PK predictions complex. Additionally, TH alters enzyme activity and systemic circulation, affecting drug clearance and distribution.

The DICE trial comprehensively evaluates dexmedetomidine’s PK parameters, including clearance rates, volume of distribution, and half-life in cooled neonates. Infants receiving dexmedetomidine during TH were closely monitored for any adverse events, sedation depth, and plasma drug concentrations using highly sensitive assays. This allowed the researchers to generate detailed PK profiles, vital for establishing dosing regimens that ensure efficacy and safety.

One of the study’s pivotal findings is that the clearance of dexmedetomidine is significantly reduced during the hypothermic phase compared to normothermia. This decrement underscores the importance of dose adjustment since standard dosages could lead to drug accumulation, increasing the risk of bradycardia or hypotension. Conversely, as rewarming commences, clearance values gradually return toward normal, necessitating further dose modulation to maintain therapeutic plasma levels.

Safety endpoints reported by Baserga and colleagues are particularly encouraging. Adverse effects typically associated with dexmedetomidine, such as profound bradycardia and hypotension, were infrequent and generally mild. Continuous cardiorespiratory monitoring revealed stable parameters in the majority of subjects, with no episodes of respiratory depression. Importantly, sedation scores indicated adequate analgesia and sedation quality, thereby validating dexmedetomidine’s dual role without the respiratory risks posed by opioids.

Beyond PK and safety, the trial explores the pharmacodynamic implications of dexmedetomidine during TH. The sedative’s anti-inflammatory and neuroprotective properties may synergize with hypothermia’s benefits, although this hypothesis requires further investigation. Animal model data suggest that alpha-2 adrenergic agonism may attenuate excitotoxic injury and oxidative stress, pathways central to neuronal death in HIE. Should future studies confirm these effects in humans, dexmedetomidine could transform neonatal encephalopathy management by enhancing neuroprotection beyond sedation.

Another critical aspect highlighted by the research is dexmedetomidine’s impact on intensive care workflow. Its relatively predictable sedation profile and minimal respiratory depression could reduce the need for mechanical ventilation, thereby lowering the risk of associated complications. Enhanced safety margins facilitate more tailored sedation strategies and potentially shortened intensive care stays, lifting both clinical and economic burdens on neonatal units.

The DICE trial’s results yield a compelling argument for revisiting current sedation protocols in TH-treated neonates. The detailed PK modeling and robust safety data provide clinicians with a scientific foundation for incorporating dexmedetomidine into standard care. Yet, the authors prudently emphasize the need for larger randomized controlled trials to conclusively determine long-term neurodevelopmental outcomes, optimal dosing schedules, and comparative efficacy versus morphine.

This research emerges amidst a broader paradigm shift in neonatal critical care, where individualized pharmacotherapy and precision medicine are gaining ground. Neonatal drug development historically suffers from a paucity of rigorous studies, often leading to off-label medication use based on extrapolation from adult data. The DICE trial represents a milestone by focusing exclusively on neonates under a specialized treatment modality, thereby refining our understanding of drug behavior in this vulnerable population.

The adoption of dexmedetomidine could align with evolving ethical standards prioritizing minimization of harm and maximal comfort in neonatal intensive care. Parents and clinicians alike are increasingly motivated to seek sedation regimens that preserve neurocognitive potential while ensuring humane care during painful and distressing therapeutic procedures.

In conclusion, the DICE trial spearheaded by Baserga et al. denotes a landmark advance in neonatology. By delineating the pharmacokinetics and safety profile of dexmedetomidine in infants undergoing therapeutic hypothermia for neonatal encephalopathy, this study charts a promising path forward. The synergy between TH and dexmedetomidine could herald a new era of neuroprotective sedation strategies that not only alleviate pain and discomfort but also contribute to improved neurological outcomes in the most fragile patients. As further validation studies emerge, dexmedetomidine stands poised to become an indispensable therapeutic tool in the neonatal intensive care arsenal.

Subject of Research: Safety and pharmacokinetics of dexmedetomidine use in neonates undergoing therapeutic hypothermia due to neonatal encephalopathy.

Article Title: Dexmedetomidine use in Infants undergoing Cooling due to neonatal Encephalopathy (DICE trial): safety and pharmacokinetics.

Article References:
Baserga, M.C., Bahr, T.M., Yang, M.J. et al. Dexmedetomidine use in Infants undergoing Cooling due to neonatal Encephalopathy (DICE trial): safety and pharmacokinetics. Pediatr Res (2026). https://doi.org/10.1038/s41390-026-05184-0

Image Credits: AI Generated

DOI: 16 June 2026

Keywords: neonatal encephalopathy, therapeutic hypothermia, dexmedetomidine, sedation, analgesia, pharmacokinetics, neonates, neuroprotection

Urban flooding has emerged as one of the most pressing environmental challenges faced by modern cities worldwide. As urbanization accelerates and impermeable surfaces replace natural landscapes, the capacity of drainage systems and natural waterways to manage stormwater dramatically decreases. This phenomenon exacerbates flood risks, leading to significant economic damage, disruption of daily life, and threats to public safety. In this context, the innovative research conducted by Dehdehi, Soleimani-Motlagh, and Haghizadeh offers a critical evaluation and in-depth analysis of the factors influencing urban flooding using advanced hydrological modeling techniques. Their work employs the Soil Conservation Service – Technical Release 20 (SCS-TR20) model and the Sacramento Soil Moisture Accounting Unit Hydrograph (SBUH) model to unravel the complexities behind flood dynamics in urban environments.

The study begins by contextualizing the incidence of urban flooding within rapidly expanding metropolitan areas. Urban landscapes are characterized by an extensive network of roads, buildings, and other paved surfaces, significantly altering the natural water cycle by accelerating runoff and reducing infiltration. The authors argue that understanding these changes requires precise hydrological models capable of simulating surface runoff, infiltration, and subsurface flow processes under varying climatic and land use scenarios. Both SCS-TR20 and SBUH models boast comprehensive frameworks that may be tailored to urban catchments, enabling the dissection of hydrological responses to precipitation events with high spatial and temporal resolution.

Fundamental to their research is the exploration of how different physical and environmental factors affect urban flooding. These include soil properties, topography, storm characteristics, land use patterns, vegetation cover, and urban infrastructure design. The SCS-TR20 model, originally developed to estimate direct runoff from small watersheds, is applied here to quantify the runoff generation process by integrating rainfall data with land surface conditions. It incorporates parameters like curve number (CN), which reflects soil infiltration capacity and land cover, to predict peak discharge during storm events. This allows the researchers to examine how changes in impervious surface area or soil moisture status may intensify or mitigate runoff production in urban catchments.

Simultaneously, the study leverages the SBUH hydrological model, a unit hydrograph-based method that simulates watershed response to rainfall by accounting for soil moisture dynamics. The SBUH model provides a mechanistic representation of subsurface flow and its contribution to streamflow, which is often overlooked in simpler runoff generation models. By embedding soil moisture accounting within the urban context, the authors can capture delayed flow components and baseflow behavior, enriching the flood prediction process. This is particularly important in urban areas where drainage infrastructure can alter natural groundwater recharge pathways.

A critical component of their methodology involves calibrating and validating these models against observed hydrological data from urban watersheds experiencing recurrent flooding. The researchers emphasize rigorous parameter optimization to enhance predictive accuracy. They adopt techniques such as sensitivity analysis to identify which parameters most significantly influence model outputs, thereby guiding priorities for data collection and urban planning interventions. The models’ outputs are then cross-verified through statistical measures, including Nash-Sutcliffe efficiency and root mean square error, confirming their robustness in simulating runoff processes in real-world urban systems.

Their findings highlight that urban flooding is not solely dependent on rainfall intensity and volume but is profoundly affected by intricate interactions between soil characteristics, land cover changes, and urban drainage infrastructure. For instance, increasing impervious surfaces significantly raises the curve number, leading to more immediate and higher runoff peaks. Moreover, poor maintenance or design flaws in stormwater systems exacerbate flooding by reducing conveyance capacity. The study also reveals that antecedent soil moisture conditions before rainfall events play a pivotal role; saturated soils contribute to quicker runoff generation and potential flash floods, emphasizing the need for integrated urban water management that considers soil moisture dynamics.

The implications of this research extend to urban planners, environmental managers, and policymakers. By elucidating how specific landscape and infrastructure features influence flood risks, the models can inform the design of resilient urban drainage networks. Incorporating green infrastructure, such as permeable pavements, rain gardens, and bio-retention basins, can modulate runoff by enhancing infiltration and delaying peak flows, a strategy validated by simulation scenarios using their models. Additionally, the work supports the advancement of early warning systems that integrate hydrological forecasts with real-time rainfall data, offering communities proactive flood risk mitigation.

Significantly, the study advances the hydrological modeling field by adapting traditional models—initially designed for rural or agricultural catchments—to the complex hydrodynamics of urban settings. This adaptation includes customizing parameter sets to account for heterogeneity in urban land use, addressing issues such as localized flooding resulting from blocked drains or topographical depressions. The dual-model approach combining SCS-TR20 and SBUH affords a more comprehensive understanding than reliance on a single modeling framework, as it captures both surface and subsurface hydrological processes with greater fidelity.

Furthermore, the research contributes to global climate change discussions by considering how altered precipitation patterns may interact with urban factors to exacerbate flooding. The authors simulate future storm scenarios based on climate projections, revealing potential increases in flood frequency and severity if urban areas do not enhance their stormwater resilience. This evidence reinforces the urgency of integrating climate adaptation measures into urban development policies, underscoring the indispensable role of hydrological models in forecasting and managing emerging flood risks.

An additional innovative aspect of this study is the use of high-resolution spatial data and advanced computational techniques to implement the hydrological models. Remote sensing technologies and geographic information systems (GIS) are applied to delineate watershed boundaries, map land cover, and analyze slope and soil properties with great precision. The incorporation of these technologies allows for dynamic model updating and supports scenario testing for various urban growth and land use change possibilities. By utilizing such data-driven methods, the authors ensure that their flood impact analyses are both spatially relevant and temporally sensitive.

The multi-faceted modeling framework also evaluates the effectiveness of different flood mitigation strategies using scenario-based simulations. For example, the researchers model the impact of increasing urban green spaces or enhancing stormwater storage capacity on reducing flood peak discharge. These simulations provide actionable insights for urban engineers and policymakers by demonstrating which interventions yield the greatest reduction in flood risks under diverse weather conditions. Consequently, their work serves as a decision-support tool to prioritize resource allocation and infrastructure investments in flood-prone urban regions.

In summary, the comprehensive evaluation and analysis conducted by Dehdehi, Soleimani-Motlagh, and Haghizadeh signify a breakthrough in understanding urban flood dynamics through integrated hydrological modeling. By leveraging the strengths of SCS-TR20 and SBUH models, their study provides a nuanced depiction of how natural, built, and climatic factors coalesce to influence flooding in cities. These insights pave the way for smarter urban water management, resilience building against extreme weather events, and sustainable urban growth.

Looking forward, the authors advocate for further refinement of hydrological models through enhanced data assimilation and coupling with hydraulic simulations to address flooding at the street and neighborhood scales. They also suggest expanding their approach to encompass socio-economic dimensions, thereby assessing the human and economic impacts of flood events alongside hydrological predictions. Such interdisciplinary integration will be vital as urban flood challenges intensify in the face of urban expansion and climate variability.

Ultimately, this pioneering research not only enriches the theoretical hydrology landscape but also offers practical tools for urban flood mitigation worldwide. As cities grapple with the escalating frequency of intense storm events, such scientifically rigorous and technologically sophisticated studies provide a beacon for safeguarding populations, infrastructure, and ecosystems from the devastating consequences of urban flooding.

Subject of Research: Evaluation and analysis of factors affecting urban flooding through hydrological modeling.

Article Title: Evaluation and analysis of the impact of factors affecting urban flooding using SCS-TR20 and SBUH hydrological models.

Article References:
Dehdehi, N., Soleimani‑Motlagh, M. & Haghizadeh, A. Evaluation and analysis of the impact of factors affecting urban flooding using SCS-TR20 and SBUH hydrological models. Sci Rep (2026). https://doi.org/10.1038/s41598-026-58279-3

Image Credits: AI Generated