Translational Research Research Articles

An Innovative Fellowship to Improve Early-Career Training in Research Translation and Communication and to Promote the Research Community

An Innovative Fellowship to Improve Early-Career Training in Research Translation and Communication and to Promote the Research Community

PFHpA alters lipid metabolism and increases the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in youth—a translational research framework

PFHpA alters lipid metabolism and increases the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in youth—a translational research framework

A Paratextual Approach to Disney’s New Mulan in China: Localization and Reception

ABSTRACT This article examines both industry-created and viewer-created paratexts of Disney’s new Mulan (2020) to shed light on the localization of industry-created paratexts for Chinese audiences, the reception of the film, and the tensions between industry-created and viewer-created paratexts in China. It reveals that Disney has localized the poster, trailers and promos of Mulan for Chinese audiences by highlighting the film’s all-star cast and creating an illusion of its faithfulness to The Ballad of Mulan, and the extolled virtues of filial piety and patriotism cherished in Chinese culture. The viewer-created paratext, danmu, of Mulan challenges the industry-created paratexts and demonstrates unfavorable reception of the film in China. It criticizes the film for its inauthenticity to The Ballad of Mulan, cultural appropriation, promotion of American values to meet the needs of English-speaking audiences for exoticness and cultural otherness. By investigating danmu as a viewer-created paratext, the present study has enriched paratextual research and reception studies in translation, media and film studies in the digital age.

Premalignant Progression in the Lung: Knowledge Gaps and Novel Opportunities for Interception of Non-Small Cell Lung Cancer. An Official American Thoracic Society Research Statement.

Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing for timely and effective intervention before cancer development. To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, along with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.

Promising animal models for amyotrophic lateral sclerosis drug discovery: a comprehensive update.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Several animal models have been generated to understand ALS pathogenesis. They have provided valuable insight into disease mechanisms and the development of therapeutic strategies. In this review, the authors provide a concise overview of simple genetic model organisms, including C. elegans, Drosophila, zebrafish, and mouse genetic models that have been generated to study ALS. They emphasize the benefits of each model and their application in translational research for discovering new chemicals, gene therapy approaches, and antibody-based strategies for treating ALS. Significant progress is being made in identifying new therapeutic targets for ALS. This progress is being enabled by promising animal models of the disease using increasingly effective genetic and pharmacological strategies. There are still challenges to be overcome in order to achieve improved success rates for translating drugs from animal models to clinics for treating ALS. Several promising future directions include the establishment of novel preclinical protocol standards, as well as the combination of animal models with human induced pluripotent stem cells (iPSCs).

Top Three Healthcare Trends in Orthopaedics Affecting Musculoskeletal Care in the Elderly.

Several trends toward patient-centered multi-care models employing translational research strategies are currently emerging in orthopaedics. These align seamlessly with epigenetics discussions in pain, a clinical approach to pain management that prioritizes tailoring healthcare to individual needs, preferences, and circumstances. Recognizing the unique genetic and epigenetic factors influencing pain perception, healthcare providers can integrate personalized insights into their patient-centered approach, offering more targeted and effective pain management strategies tailored to each individual's experience. Custom 3D-printing technologies may also become increasingly relevant to more effectively and reliably treat painful degenerative structural abnormalities. They are expected to go hand-in-hand with the precision medicine redefinition of musculoskeletal care. More effective analysis of surgeons' clinical decision-making and patients' perception of high-value orthopaedic care is needed. Shared Decision Making (SDM) is critical to identifying the best solution for each patient and improving stakeholders' understanding of factors influencing the diverse prioritizing values of surgical or non-surgical treatments by payers, systems, and other providers. Identifying high-value orthopaedic surgeries via effective SDM in orthopedic surgery requires more than just presenting patients with information. The Rasch analysis of patient expectations can provide this nuanced approach that involves understanding patient values, addressing misconceptions, and aligning surgical recommendations with patient-specific goals. Optimizing orthopaedic treatment within the patient-centered framework can drive innovation in reimbursement policies that support the field more broadly. Research on separating high-value from low-value orthopaedic procedures may likely impact healthcare decision- makers' resource allocation.

Engineering a dysbiotic biofilm model for testing root caries interventions through microbial modulation

BackgroundThis study aimed to engineer and optimise a dysbiotic biofilm model to develop in vitro root caries for investigating microbial modulation strategies. The model involved growing complex biofilms from a saliva inoculum collected from four volunteers using two strategies. In the first strategy (“pre-treatment strategy”), bovine root slabs were used, and two natural compounds were incorporated at time 0 of the 10-day biofilm experiment, which included sucrose cycles mimicking the cariogenic environment. In the second strategy (“post-treatment strategy”), mature biofilms were grown in a modified Calgary biofilm device coated with collagen and hydroxyapatite for 7 days and then were exposed to the same natural compounds. The metatranscriptome of each biofilm was then determined and analysed. Collagenase activity was examined, and the biofilms and dentine were imaged using confocal and scanning electron microscopy (SEM). Mineral loss and lesion formation were confirmed through micro-computed tomography (μ-CT).ResultsThe pH confirmed the cariogenic condition. In the metatranscriptome, we achieved a biofilm compositional complexity, showing a great diversity of the metabolically active microbiome in both pre- and post-treatment strategies, including reads mapped to microorganisms other than bacteria, such as archaea and viruses. Carbohydrate esterases had increased expression in the post-treated biofilms and in samples without sugar cycles, while glucosyltransferases were highly expressed in the presence of sucrose cycles. Enrichment for functions related to nitrogen compound metabolism and organic cyclic component metabolism in groups without sucrose compared to the sucrose-treated group. Pre-treatment of the roots with cranberry reduced microbial viability and gelatinase (but not collagenase) activity (p < 0.05). SEM images showed the complexity of biofilms was maintained, with a thick extracellular polysaccharides layer.ConclusionsThis root caries model was optimized to produce complex cariogenic biofilms and root caries-like lesions, and could be used to test microbial modulation in vitro. Pre-treatments before biofilm development and cariogenic challenges were more effective than post-treatments. The clinical significance lies in the potential to apply the findings to develop varnish products for post-professional tooth prophylaxis, aiming at implementing a strategy for dysbiosis reversal in translational research.2cRgxuoMbmgt6TZPkgExXQVideo

Systematic review and feasibility study on pre-analytical factors and genomic analyses on archival formalin-fixed paraffin-embedded breast cancer tissue

Formalin-fixed paraffin-embedded (FFPE) tissue represents a valuable source for translational cancer research. However, the widespread application of various downstream methods remains challenging. Here, we aimed to assess the feasibility of a genomic and gene expression analysis workflow using FFPE breast cancer (BC) tissue. We conducted a systematic literature review for the assessment of concordance between FFPE and fresh-frozen matched tissue samples derived from patients with BC for DNA and RNA downstream applications. The analytical performance of three different nucleic acid extraction kits on FFPE BC clinical samples was compared. We also applied a newly developed targeted DNA Next-Generation Sequencing (NGS) 370-gene panel and the nCounter BC360® platform on simultaneously extracted DNA and RNA, respectively, using FFPE tissue from a phase II clinical trial. Of the 3701 initial search results, 40 articles were included in the systematic review. High degree of concordance was observed in various downstream application platforms. Moreover, the performance of simultaneous DNA/RNA extraction kit was demonstrated with targeted DNA NGS and gene expression profiling. Exclusion of variants below 5% variant allele frequency was essential to overcome FFPE-induced artefacts. Targeted genomic analyses were feasible in simultaneously extracted DNA/RNA from FFPE material, providing insights for their implementation in clinical trials/cohorts.

Metabolomic prediction of breast cancer treatment induced neurological and metabolic toxicities.

Long-term treatment-related toxicities, such as neurological and metabolic toxicities, are major issues in breast cancer. We investigated the interest of metabolomic profiling to predict toxicities. Untargeted high-resolution metabolomic profiles of 992 patients with ER+/HER2- breast cancer from the prospective CANTO cohort were acquired (n=1935 metabolites). A residual-based modeling strategy with a discovery and validation cohort was used to benchmark machine learning algorithms, taking into account confounding variables. Adaptive LASSO has a good predictive performance, has limited optimism bias, and allows the selection of metabolites of interest for future translational research. The addition of low-frequency metabolites and non-annotated metabolites increases the predictive power. Metabolomics adds extra performance to clinical variables to predict various neurological and metabolic toxicity profiles. Untargeted high-resolution metabolomics allows better toxicity prediction by considering environmental exposure, metabolites linked to microbiota, and low-frequency metabolites.

Exploring the Spectrum of Long Non-Coding RNA CARMN in Physiological and Pathological Contexts

Cardiac mesoderm enhancer-associated non-coding RNA (CARMN), an evolutionarily conserved long non-coding RNA (lncRNA), serves as the host gene for the miR143/145 cluster. It plays a crucial role in cardiovascular cell differentiation and the maintenance of vascular smooth muscle cell (VSMC) homeostasis, which are vital for normal physiological processes. Specifically, CARMN is associated with the pathological progression of cardiovascular diseases such as atherosclerosis, abdominal aortic aneurysm, and chronic heart failure. Moreover, it acts as a tumor suppressor in various cancers, including hepatocellular carcinoma, bladder cancer, and breast cancer, highlighting its potential as a beneficial biomarker and therapeutic target. This review provides a detailed examination of the roles of CARMN, its evolutionary conservation, expression patterns, and regulatory mechanisms. It also outlines its significant implications in the diagnosis, prognosis, and treatment of these diseases, underscoring the need for further translational research to exploit its clinical potential.

The bench to community initiative: community-based participatory research model for translating research discoveries into community solutions

Community-based participatory research (CBPR) is an effective methodology for translating research findings from academia to community interventions. The Bench to Community Initiative (BCI), a CBPR program, builds on prior research to engage stakeholders across multiple disciplines with the goal of disseminating interventions to reduce breast cancer disparities and improve quality of life of Black communities.MethodsThe BCI program was established to understand sociocultural determinants of personal care product use, evaluate the biological impact of endocrine disrupting chemicals, and develop community interventions. The three pillars of the program include research, outreach and engagement as well as advocacy activities. The research pillar of the BCI includes development of multidisciplinary partnerships to understand the sociocultural and biological determinants of harmful chemical (e.g., endocrine disrupting chemicals) exposures from personal care products and to implement community interventions. The outreach and engagement pillar includes education and translation of research into behavioral practice. The research conducted through the initiative provides the foundation for advocacy engagement with applicable community-based organizations. Essential to the mission of the BCI is the participation of community members and trainees from underrepresented backgrounds who are affected by breast cancer disparities.ResultsTwo behavioral interventions will be developed building on prior research on environmental exposures with the focus on personal care products including findings from the BCI. In person and virtual education activities include tabling at community events with do-it-yourself product demonstrations, Salon Conversations—a virtual platform used to bring awareness, education, and pilot behavior change interventions, biennial symposiums, and social media engagement. BCI’s community advisory board members support activities across the three pillars, while trainees participate in personal and professional activities that enhance their skills in research translation.DiscussionThis paper highlights the three pillars of the BCI, lessons learned, testimonies from community advisory board members and trainees on the impact of the initiative, as well as BCI’s mission driven approaches to achieving health equity.

Travis I. Thompson (1937-2023).

Travis I. Thompson was born on July 20, 1937, in Minneapolis to William and Loretta Thompson. Travis completed his BA (1958), MA (1961), and PhD (1961) degrees all at the University of Minnesota in Psychology, with postdoctoral work at the University of Maryland with Joseph V. Brady and at Cambridge University (United Kingdom) with Robert Hinde. Travis began his academic career at the University of Minnesota in 1963 rising to the rank of professor of Psychiatry and Neurology and Psychology and Pharmacology in 1969. A prolific writer, Travis, published more than 200 articles and chapters and 30 books including four on the translation of research on autism for parents, teachers, and professionals. He had a knack for motivating people to believe in their ability to grow and develop as researchers and work collaboratively on complex issues related to intellectual and developmental disabilities (IDD). Travis was part of the intellectual force founding the area now known as behavioral pharmacology. Throughout his career, Travis remained deeply curious about how basic principles could be used to understand how things worked-his approach was to identify the functional pieces, take them apart, and put them back together. He wanted that activity to matter. It did. He is survived by his wife, Anneke, four children, and seven grandchildren. He died in Roseville, Minnesota, on August 2, 2023, at the age of 85. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Evidence, Policy, Education, and Neuroscience—The State of Play in the UK

AbstractIn this article, we give an overview of translational educational neuroscience (mind, brain, and education) in the United Kingdom. We consider the state of translation, describing respectively the state of the dialogue between researchers and educators, the state of evaluation of approaches to improve educational outcomes, and the state of innovation in research translation. We consider the teacher perspective. What do UK teachers think about educational neuroscience and its potential for informing classroom practice, and how do ideas about pedagogical approaches feature among their everyday concerns? We describe the results of a recent survey from a representative sample of over 1,000 UK teachers, and a case study of a UK high school teacher who employs educational neuroscience in his practice and what this entails. Lastly, we consider the policy perspective and assess the recent move by the UK government to introduce knowledge of cognitive science into initial and early‐career teacher training.

Neuromicrobiology Comes of Age: The Multifaceted Interactions between the Microbiome and the Nervous System.

The past decade has seen an explosion in our knowledge about the interactions between gut microbiota, the central nervous system, and the immune system. The gut-brain axis has recently gained much attention due to its role in regulating host physiology. This review explores recent findings concerning potential pathways linking the gut-brain axis to the initiation, pathophysiology, and development of neurological disorders. Our objective of this work is to uncover causative factors and pinpoint particular pathways and therapeutic targets that may facilitate the translation of experimental animal research into practical applications for human patients. We highlight three distinct yet interrelated mechanisms: (1) disruptions of both the intestinal and blood-brain barriers, (2) persistent neuroinflammation, and (3) the role of the vagus nerve.

Abstract Introduction

Abstract The 6th Kidney Cancer Research Summit (KCRS) took place on July 11th &amp; 12th, 2024 as a hybrid event both in Boston, Massachusetts at the InterContinental Boston, and virtually via Zoom webinar. The conference format consists of oral presentations in an intimate setting that enables dynamic discussion among attendees. The meeting began with a keynote titled “How the Air We Breathe Can Impact Cancer,” showing the biological processes underlying how airborne microparticles drive inflammatory processes that fuel tumorigenesis. Sessions included Exploring Novel Drug Targets for RCC, Novel Imaging and Biomarkers to Guide RCC Patient Management, State of the Science, Trials in Progress, Clinical and Scientific Updates in Kidney Cancer, Immunotherapy Advances and Research, Oral Abstracts, and Rapid Abstracts. The KCRS was inaugurated in 2019 to congregate the community of researchers conducting projects involving kidney cancer with clinicians, industry partners, and patient advocates in order to foster new collaborations and generate constructive feedback. KCRS is funded through sponsors, partnerships, and grassroots supporters organized by KidneyCAN, a nationwide network of kidney cancer patients, caregivers, and family members who are committed to accelerating cures for kidney cancer. Basic through translational and clinical research are included, and the program is centered on projects funded through the Department of Defense’s Kidney Cancer Research Program awards. The goal is to give current and future projects the best chance to succeed and ensure the orientation of goals towards raising the standard of care and improving patient outcomes across all histological subtypes and stages of this disease. This supplement contains a complete list of scheduled abstract presentations that were accepted as of June 17th, 2024. Please be aware that some abstracts may have been withdrawn or rescheduled at the authors’ request.

Time to reach equilibrium deep body temperatures in young and older adults resting in the heat: A descriptive secondary analysis.

It is commonly thought that steady-state thermoregulatory responses are achieved within 30-90 min of compensable heat stress. However, this assumption is based on measurements of whole-body heat exchange during exercise, which stabilize (equilibrate) more rapidly than deep body temperatures, especially under resting conditions. To support the design of ecologically relevant heat exposure studies, we quantified equilibrium times for deep body temperature, as indexed by rectal temperature, in young and older adults resting in the heat. We also evaluated the lag in rectal temperature equilibrium relative to whole-body heat storage (direct calorimetry). Equilibrium times were estimated with data from two laboratory-based trials (NCT04353076 and NCT04348630) in which 83 adults aged 19-80 years (34 female) were exposed to simulated heat wave conditions for 8-9 hours. When assessed on the group level, it took rectal temperature 3.3 [bootstrap 95%CI: 2.9 to 3.9] hours to reach thermal equilibrium (<0.05°C/hour rate of change) in young adults exposed to 40°C, 9% relative humidity (RH). In older adults, who were exposed to a greater range of conditions (31-40°C, 9-45% RH), equilibrium times were longer, ranging from 4.4 [3.8 to 5.3] to 5.2 [4.9 to 5.4] hours. Furthermore, rectal temperature equilibrium was delayed 0.9 [0.5 to 1.4] and 1.8 [0.9 to 2.7] hours compared to whole-body heat storage in young and older adults, respectively (only assessed in 40°C, 9% RH). Individual level equilibrium times ranged from 1-8 hours. These findings highlight the importance of ecologically relevant exposure durations in translational research assessing the physiological impacts of hot weather.

Unraveling the influence of LncRNA in gastric cancer pathogenesis: a comprehensive review focus on signaling pathways interplay.

Gastric cancers (GCs) are among the most common and fatal malignancies in the world. Despite our increasing understanding of the molecular mechanisms underlying GC, further biomarkers are still needed for more in-depth examination, focused prognosis, and treatment. GC is one among the long non-coding RNAs, or lncRNAs, that have emerged as key regulators of the pathophysiology of cancer. This comprehensive review focuses on the diverse functions of long noncoding RNAs (lncRNAs) in the development of GC and their interactions with important intracellular signaling pathways. LncRNAs affect GC-related carcinogenic signaling cascades including pathways for EGFR, PI3K/AKT/mTOR, p53, Wnt/β-catenin, JAK/STAT, Hedgehog, NF-κB, and hypoxia-inducible factor. Dysregulated long non-coding RNA (lncRNA) expression has been associated with multiple characteristics of cancer, such as extended growth, apoptosis resistance, enhanced invasion and metastasis, angiogenesis, and therapy resistance. For instance, lncRNAs such as HOTAIR, MALAT1, and H19 promote the development of GC via altering these pathways. Beyond their main roles, GC lncRNAs exhibit potential as diagnostic and prognostic biomarkers. The overview discusses CRISPR/Cas9 genome-modifying methods, antisense oligonucleotides, small molecules, and RNA interference as potential therapeutic approaches to regulate the expression of long noncoding RNAs (lncRNAs). An in-depth discussion of the intricate functions that lncRNAs play in the development of the majority of stomach malignancies is provided in this review. It provides the groundwork for future translational research in lncRNA-based whole processes toward GC by highlighting their carcinogenic effects, regulatory roles in significant signaling cascades, and practical scientific uses as biomarkers and therapeutic targets.

Poor sleep and decreased cortical thickness in veterans with mild traumatic brain injury and post-traumatic stress disorder

BackgroundPoor sleep quality has been associated with changes in brain volume among veterans, particularly those who have experienced mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). This study sought to investigate (1) whether poor sleep quality is associated with decreased cortical thickness in Iraq and Afghanistan war veterans, and (2) whether these associations differ topographically depending on the presence or absence of mTBI and PTSD.MethodsA sample of 440 post-9/11 era U.S. veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders study at VA Boston, MA from 2010 to 2022 was included in the study. We examined the relationship between sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), and cortical thickness in veterans with mTBI (n = 57), PTSD (n = 110), comorbid mTBI and PTSD (n = 129), and neither PTSD nor mTBI (n = 144). To determine the topographical relationship between subjective sleep quality and cortical thickness in each diagnostic group, we employed a General Linear Model (GLM) at each vertex on the cortical mantle. The extent of topographical overlap between the resulting statistical maps was assessed using Dice coefficients.ResultsThere were no significant associations between PSQI and cortical thickness in the group without PTSD or mTBI (n = 144) or in the PTSD-only group (n = 110). In the mTBI-only group (n = 57), lower sleep quality was significantly associated with reduced thickness bilaterally in frontal, cingulate, and precuneus regions, as well as in the right parietal and temporal regions (β = −0.0137, P < 0.0005). In the comorbid mTBI and PTSD group (n = 129), significant associations were observed bilaterally in frontal, precentral, and precuneus regions, in the left cingulate and the right parietal regions (β = −0.0094, P < 0.0005). Interaction analysis revealed that there was a stronger relationship between poor sleep quality and decreased cortical thickness in individuals with mTBI (n = 186) compared to those without mTBI (n = 254) specifically in the frontal and cingulate regions (β = −0.0077, P < 0.0005).ConclusionsThis study demonstrates a significant relationship between poor sleep quality and lower cortical thickness primarily within frontal regions among individuals with both isolated mTBI or comorbid diagnoses of mTBI and PTSD. Thus, if directionality is established in longitudinal and interventional studies, it may be crucial to consider addressing sleep in the treatment of veterans who have sustained mTBI.

Efficient breeding system of infertile Niemann-Pick disease type C model mice by in vitro fertilization and embryo transfer.

Niemann-Pick disease type C (NPC) is a lethal genetic disease with mutations in NPC1 or NPC2 gene. Npc1-deficient (Npc1-/-) mice have been used as a model for NPC pathogenesis to develop novel therapies for NPC. However, Npc1-/- mice are infertile; thus, securing sufficient numbers for translational research is difficult. Hence, we attempted reproductive engineering techniques such as in vitro fertilization (IVF) and sperm cryopreservation. For the first time, we succeeded in producing fertilized oocytes via IVF using male and female Npc1-/- mice. Fertilized oocytes were also obtained via IVF using cryopreserved sperm from Npc1-/- mice. The obtained fertilized oocytes normally developed into live pups via embryo transfer, and they eventually exhibited NPC pathogenesis. These findings are useful for generating an efficient breeding system that overcomes the reproductive challenges of Npc1-/- mice and will contribute to developing novel therapeutic methods using NPC model mice.

75 WIRE: Window of Opportunity Clinical Trials Platform for Evaluation of Novel Treatments Strategies in Renal Cell Cancer

Abstract Background Despite the success of immunotherapy and VEGFR directed tyrosine kinase inhibitors (TKIs) for the treatment of renal cell carcinoma (RCC), a significant proportion of patients display primary or secondary resistance to systemic therapy. New treatment approaches are needed for these patients. Pre-surgical clinical trials allow us to study the effects of cancer treatment on the tumour microenvironment, comparing baseline biopsy with post-treatment nephrectomy in a ‘window of opportunity’ study. The results may give us insight into the mechanisms of new cancer therapies, that may be advanced into further clinical trials. Methods The WIRE trial (NCT03741426) is a phase II, multi-centre, multi-arm, non-randomised, neoadjuvant clinical trial platform. The overall aim of the trial is proof of mechanism for new RCC therapies. There are five investigational arms: 1. Cediranib (a VEGFR directed TKI), 2. Cediranib + Olaparib (a PARP inhibitor), 3. Olaparib, 4. Volrustomig (anti PD-1/CTLA-4 bispecific) and 5. Rilvegostomig (anti PD-1/TIGIT bispecific). The study uses a Bayesian adaptive design to optimise recruitment, with pre-specified criteria assessed at interim analyses to stop for futility, continue recruitment to that arm, or move to the next investigational arm. Eligible patients have cT1b+, cN0/1, cM0/1 clear cell RCC, planning to undergo surgery, without medical contraindication to trial therapy. Patients undergo baseline biopsy to confirm clear cell RCC and multiparametric dynamic contrast enhanced (DCE) MRI scan of the primary tumour. For tablet arms 1-3, patients receive at least 14 days of investigational medicinal product (IMP). For immunotherapy arms 4 &amp; 5, patients receive one infusion of IMP. The tumour is re-evaluated by DCE-MRI immediately before surgery. At nephrectomy, multi-region tissue sampling from the tumour is performed both pre-arterial ligation and post resection. Serial translational blood and urine samples are collected before, during and after treatment. The primary endpoint for arms 1-3 is a ≥30% reduction in DCE-MRI assessed capillary permeability (Ktrans) compared to baseline. The primary endpoint for arms 4 &amp; 5 is a ≥30% increase in IHC assessed CD8+ T cell density comparing the resected tumour to baseline biopsy. Secondary endpoints include RECIST v1.1 primary tumour response and adverse events. A comprehensive translational science programme accompanies the trial, which will assess the tumour microenvironment and peripheral blood response to therapy, using techniques including imaging mass cytometry and single cell RNA sequencing. This will allow us to gain a deep understanding of mechanisms of response in each investigational arm. To date, arms 1 &amp; 2 have completed recruitment, and arm 3 is actively recruiting. Conclusions WIRE offers a unique opportunity to investigate the mechanisms of new therapies for RCC. Successful completion of these peri-surgical studies depends on co-ordination between many specialties, including surgery, oncology, radiology, and pathology. The adaptive design allows for efficient allocation of patients to treatment arms to generate optimal data for each IMP. WIRE may identify novel biomarkers of response and toxicity, to inform treatment selection for patients. The data generated will be a foundation for further trials of these IMPs in advanced disease.