The tumor microenvironment (TME) plays a pivotal role in immuno-oncology, influencing cancer progression and treatment outcomes. Among its components, stromal tumor-infiltrating lymphocytes (sTILs) represent important prognostic and predictive biomarkers in breast cancer. However, visual assessment of sTILs is complex, time-consuming, and subject to inter-observer variability. To address these challenges, we propose an AI-based framework for sTILs quantification in hematoxylin and eosin (H&E)-stained breast cancer histopathological images across different molecular subtypes, in accordance with the recommendations of the International Immuno-Oncology Biomarker Working Group (IIOBWG). The framework integrates two parallel and explainable segmentation models trained on multi-center data: an attention-based model for TILs detection and a stroma segmentation model designed to identify both tumoral and infiltrated stromal regions as a unified clinically relevant compartment. The resulting segmentation outputs are combined through a scanner resolution-aware quantification algorithm, enabling robust sTILs scoring across data acquired from different scanners and institutions. The proposed framework was externally validated on two independent private datasets comprising 60 and 112 whole-slide images with expert-annotated Region Of Interests (ROIs). Strong agreement with expert pathologist scoring was achieved (Pearson correlation up to 0.73; Concordance Correlation Coefficient (CCC) up to 0.72), and the framework consistently outperformed state-of-the-art approaches when evaluated on the same data. These results demonstrate that the proposed framework provides a reliable, efficient, and scalable solution for standardized sTILs quantification, supporting its potential utility in both clinical practice and translational research.

APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. Despite global efforts to promote resilience, delay cognitive decline, and slow aging, APOE ε2, one of the most robust resilience-associated variants, remains relatively underexplored in translational research. Exceptional longevity offers a window into cognitive trajectories. We present clinical, cognitive and neuroimaging data from five APOE ε2/ε3 siblings aged 94-105. Cognition ranged from normal to mild dementia. MRI showed less atrophy than expected for advanced age, and FDG-PET revealed preserved metabolism. Findings demonstrate APOE ε2-associated resilience in the oldest-old and offer insight into mechanisms of exceptional cognitive aging with potential translational relevance.

Protein substitutes used in the treatment of phenylketonuria distinctly modulate gut nutrient absorption and bacterial growth: An in vitro study.

Novel strategies to overcome the blood-brain barrier in triple-negative breast cancer brain metastases.

The circadian rhythm system plays an essential role in maintaining skeletal homeostasis, yet the precise impact of circadian rhythm abnormalities on bone mineral density (BMD) remains poorly understood. In this study, we systematically investigated the effects of rhythm disruption on bone metabolism by establishing murine models exposed to winter-simulated extended darkness (8-h light:16-h dark) and severe non-24-h light-dark cycles (8L:8D, 6L:6D, and 4L:4D). Our structural and histological analyses revealed that abnormal circadian rhythms profoundly uncouple bone remodeling, leading to a precipitous decline in trabecular bone mass. Crucially, we demonstrated that enhanced osteoclast activity due to the extended period of darkness in winter increases the risk of fractures, and this skeletal deterioration is further exacerbated under increasingly fragmented non-24-h rhythms. Mechanistically, circadian misalignment induced a severe downregulation of the Sirt3-SOD2 signaling pathway in bone tissue, which released physiological constraints on RANKL expression and subsequently drove rampant osteoclastogenesis. Pharmacological intervention with the endogenous circadian synchronizer melatonin partially mitigated this rhythm-disrupted bone loss by restoring Sirt3 expression and predominantly enhancing osteoblast anabolism; however, its capacity to directly suppress rhythm-induced osteoclast hyperactivation was limited. Furthermore, co-treatment with the Sirt3 inhibitor 3-TYP abolished the osteoprotective effects of melatonin by concurrently impairing osteoblast function. Collectively, these findings identify circadian rhythm disruption as a critical intrinsic driver of BMD decline. This chronobiological perspective elucidates that photoperiod-induced circadian disruptions may act as a risk factor for diminished bone density by driving osteoclastogenesis, warranting further translational research in humans.

Rationale and study protocol for a randomized controlled MIND diet feeding trial for breast cancer-related cognitive impairment.

Charles Friedman's Fundamental Theorem of Biomedical Informatics holds that a person working in partnership with an information resource outperforms that same person unassisted. Since its publication, advances in artificial intelligence (AI), adaptive learning systems, and large-scale data infrastructures have transformed the biomedical ecosystem, extending informatics beyond clinical care into domains such as public health, consumer health, translational science, and the broader life sciences. Such expansion has further underscored the importance of the Fundamental Theorem while also elucidating ways it can be expanded to meet current needs. To reassess and extend the Fundamental Theorem for the AI era in a manner that preserves its conceptual strength while broadening its applicability across an evolved and more complex biomedical ecosystem. This Viewpoint synthesizes empirical evidence and sociotechnical theory related to human-AI collaboration, learning health systems (LHS), learning public health systems (LPHS), AI governance, and systems science to contextualize the Fundamental Theorem within such contemporary frameworks. We argue that the unit of analysis of the Fundamental Theorem should shift from individuals and tools to adaptive sociotechnical systems spanning clinical care, public health, translational research, consumer engagement, and life sciences innovation. We propose an expanded theorem: A learning biomedical ecosystem that continuously optimizes human-AI collaboration will outperform humans or AI alone. This evolution builds directly upon Friedman's original theorem, reaffirming its human-centered foundation, while incorporating AI-enabled computation, adaptive learning, and systems-level integration across the modern biomedical enterprise.

Aumolertinib with or without chemotherapy in EGFR-mutated advanced non-small-cell lung cancer (AENEAS2): an open-label, multicentre, randomised, controlled, phase 3 trial.

ABCA4-associated retinopathies (Stargardt disease) are the most common inherited macular dystrophy and a leading cause of early onset central vision loss. Biallelic pathogenic variants in the ABCA4 gene cause impaired clearance of retinoid byproducts, leading to toxic bisretinoid accumulation, retinal pigment epithelium dysfunction, and progressive photoreceptor degeneration. Clinical presentation and disease progression are highly heterogeneous, largely influenced by genotype, age at onset, and environmental modifiers. Current management remains supportive and includes low-vision rehabilitation and counseling. Recent advances in molecular genetics, retinal imaging, and translational science have substantially expanded the therapeutic pipeline for ABCA4 retinopathy. Disease-modifying strategies under active investigation include visual-cycle modulation, deuterated vitamin A analogs, retinol-binding protein antagonists, gene augmentation and editing approaches, antisense oligonucleotides, and cell-based regenerative therapies. Several pharmacologic agents have demonstrated promising structural outcomes in clinical trials, while gene-based and regenerative approaches continue to evolve amid challenges related to gene size, delivery efficiency, and long-term safety. Optogenetic therapy has emerged as a gene-agnostic option for functional vision restoration in advanced disease stages. This review provides an integrated overview of ABCA4 retinopathy, summarizing disease mechanisms, current management strategies, emerging therapies, and the evolving clinical trial landscape. Emphasis is placed on stage-adapted treatment paradigms, appropriate monitoring endpoints, and the potential role of combination therapies. Ongoing innovation and precision-based approaches offer cautious optimism for durable disease modification and functional preservation in this currently untreatable condition.

Evidence-based nutrition guidance for female athletes remains limited relative to that available for males; in part, this has contributed to widespread reliance on social media for dietary information. Whilst social media can enhance health communication, it also facilitates the rapid dissemination of unverified, commercially driven nutrition claims. This narrative review critically synthesises the current scientific literature underpinning four prevalent claims targeting nutrition close to exercise for active females; (1) fasted training is harmful for all females, (2) menstrual cycle-related hormonal fluctuations require sex-specific hydration strategies, (3) carbohydrate differences by sex and menstrual cycle phase, and (4) precise protein timing is essential for optimal adaptation in females. Despite social media and 'influencer' claims of no evidence in humans for many of the claims, there is some, albeit limited, evidence. This review evaluates the available research and the evidence supporting these claims to provide practical advice for active females. Collectively, this review demonstrates that many widely circulated nutrition claims directed at active females lack robust scientific support. The findings emphasise the importance of individual context, including training load, energy availability, environmental conditions and total dietary intake, over rigid, sex-specific nutrition rules. Improved translation of female-specific sports nutrition research into accurate, accessible public messaging is urgently needed to counter persistent misinformation in digital media.

Sarcomas are rare, diverse malignancies with limited therapeutic options and poor clinical outcomes. Preclinical models that preserve tumour biology are urgently needed to advance mechanistic understanding and functional precision oncology. We established and comprehensively characterized 29 early-passage patient-derived sarcoma cell (PDC) cultures from 19 patients, representing 11 sarcoma subtypes. Multi-region and multi-site sampling enabled generation of PDCs from spatially distinct areas of individual tumours and from matched primary, recurrent and metastatic lesions. PDCs underwent genomic, transcriptomic and proteomic profiling alongside extracellular vesicle (EV) biomarker evaluation and phenotypic and drug-response assays. Copy-number variant (CNV) analysis revealed recurrent alterations affecting key regulators of cell cycle control and growth signalling. Bulk RNA-sequencing captured substantial inter- and intra-subtype heterogeneity. Proteomic and EV analyses recapitulated subtype- and site-specific differences. A functional drug screen of 38 clinically relevant and investigational agents identified both shared and divergent therapeutic vulnerabilities in the different PDCs. These results demonstrate that early-passage sarcoma PDCs can be regarded as biologically faithful and experimentally tractable models that capture lineage identity, tumour evolution and functional heterogeneity. Integrated multi-omic and functional profiling reveals therapeutic vulnerabilities not evident from genomic data only, supporting PDCs as valuable platforms for translational sarcoma research. A PDC biobank that addresses a critical gap in sarcoma research. Investigation of intra-patient and inter-patient heterogeneity. Comprehensive characterization shows truthful recapitulation of sarcoma features. Functional assays highlight the importance of functional models in cancer research.

From Oxidative Stress to Pain Modulation With Melatonin in Neonatal and Pediatric Care.

Dietary trials methodology in the field of translational gastrointestinal research is fraught with constraints, relating to cost, practicalities of executing dietary trials, and the particulars of manipulating foods that often cannot be overcome. As such, dietary interventions may be unfairly judged as low quality. However, dietary trials are commonly poorly designed, based principally on drug trial methodology, which is often not appropriate in the setting of food, has a very different composition, and is not delivered like pharmaceuticals. This risks accurate interpretation of data and a lack of translatability to clinic. Careful attention should be given to the design of dietary trials to ensure studies remain high quality and clinically relevant. This review summarizes the key factors necessary for consideration when executing a well-designed dietary trial for gastrointestinal conditions and examples of how they have been used and reported on. Key factors include modeling dietary composition to meet the research question, appraising pre-exposure diets and their impact on the study, interpretation and potential use of placebo and nocebo effects, and the use of sham diets. Finally, measuring and reporting on blinding and adherence, which is essential, as for all trials methodology.

This study aimed to systematically characterize the global research landscape, collaboration patterns, knowledge structure, and emerging hotspots of glucagon-like peptide-1 receptor agonists in neurodegenerative diseases using bibliometric methods. Publications related to glucagon-like peptide-1 receptor agonists and neurodegenerative diseases were retrieved from the Web of Science Core Collection from 2006 to 2025. Only English-language articles and reviews were included. Bibliometric analyses were performed using Bibliometrix, VOSviewer, and CiteSpace to evaluate annual publication trends, country and institutional contributions, author collaborations, journal distribution, citation structures, keyword co-occurrence, thematic evolution, and citation bursts. A Scopus-based sensitivity analysis was conducted to assess the robustness of the main bibliometric findings. A total of 1,202 publications were included, with annual output increasing from 2 in 2006 to 241 in 2025, particularly after 2020. China, the USA, and England were the leading contributors and major collaboration hubs. Shanxi Medical University, Lancaster University, and the National Institute on Aging were among the most productive institutions, while major journals included International Journal of Molecular Sciences, Neuropharmacology, European Journal of Pharmacology, Frontiers in Endocrinology, Frontiers in Pharmacology, and Journal of Alzheimer's Disease. Keyword and citation analyses indicated a thematic shift from exendin-4, Alzheimer's disease, Parkinson's disease, and neuroprotection toward semaglutide, neuroinflammation, cognitive impairment, clinical efficacy, evidence synthesis, and combination therapy. Research on glucagon-like peptide-1 receptor agonists in neurodegenerative diseases has expanded rapidly over the past two decades. Current bibliometric evidence suggests that this field has evolved from preclinical exploration toward broader translational and clinical research, with increasing attention to neuroinflammation, metabolic dysfunction, cognitive outcomes, and newer incretin-based therapies. However, the therapeutic implications of glucagon-like peptide-1 receptor agonists for neurodegenerative diseases remain to be further validated by high-quality mechanistic studies and well-designed clinical trials.

Hypoxia-inducible factor 2α (HIF2α; also known as endothelial PAS domain-containing protein 1) had long been considered an undruggable transcription factor until the discovery of an allosteric pocket within its PAS-B domain enabled the development of selective small-molecule antagonists. Belzutifan, the first-in-class HIF2α inhibitor, has since demonstrated substantial efficacy in patients with von Hippel-Lindau (VHL) disease-associated tumours, sporadic clear-cell renal cell carcinoma (ccRCC), and pheochromocytoma or paraganglioma, thereby validating HIF2α as a therapeutic target in patients with cancer. In this Review, we summarize the biology of the VHL-HIF signalling pathway, the structural basis for HIF2α druggability and the clinical milestones leading to the multiple regulatory approvals of belzutifan. We also highlight emerging data on other small-molecule inhibitors, RNA interference approaches and indirect modulators that have the potential to expand the scope of HIF pathway suppression. Combination strategies offer opportunities to enhance efficacy and overcome resistance; however, key challenges remain, including the identification of predictive biomarkers, mechanisms of primary and acquired resistance, and optimal management approaches for on-target toxicities such as anaemia and hypoxia. Finally, we discuss the increasing potential of HIF2α inhibition beyond kidney cancer, including its role in hypoxia-adapted malignancies, and outline priorities for future translational and clinical research.

Neuro-tumor-immune crosstalk in pancreatic cancer: Mechanisms and therapeutic insights.

Prostate cancer is a common cancer in males and there is an urgent unmet clinical need to improve early diagnosis and identify new treatments for advanced disease. Despite huge progress in understanding changes to the genome and proteome in prostate cancer, there is a relative delay in revealing the full aspects of the prostate cancer glycome and glycoproteome. Glycobiology has been fundamental in recent discoveries in the medical field, including translational cancer research. Glycans functionally contribute to the cancer hallmarks and serve as important diagnostic biomarkers and targets for therapeutic intervention. Changes to glycans are common in prostate cancer and include increased branching of complex N-glycans, changes in sialylation, increased fucosylation, altered PSA glycosylation and the expression of truncated O-glycans. This review discusses the role of glycans in fundamental mechanisms controlling prostate cancer growth, metastasis and immune evasion. Emphasis is placed on discoveries made during the last decade, including new insights provided by N-glycan imaging mass spectrometry (IMS) profiling of prostate cancer tissues, new discoveries into the role of aberrant glycosylation in prostate tumour biology, as well as recent studies investigating glycans, glycosyltransferase enzymes and glycan binding proteins as therapeutic targets.

Medical imaging relies on tracer materials to enable accurate visualization and diagnosis of diseases. Magnetic Particle Imaging (MPI) is an innovative tomographic modality that offers exceptional sensitivity and temporal resolution. These characteristics make MPI particularly promising for clinical applications such as real-time vascular and perfusion imaging, tumor detection, and intraoperative guidance. However, MPI performance has so far been limited by the quality of available tracers, as conventional chemical synthesis provides only restricted control over the size, shape, and magnetic properties of iron oxide nanoparticles. Biogenic magnetic nanoparticles, so-called magnetosomes, produced by magnetotactic bacteria, represent a compelling alternative. Magnetosome biosynthesis is fully genetically encoded, enabling the natural formation of magnetite nanoparticles with uniform size and morphology, which is difficult to achieve through chemical synthesis. Moreover, genetic engineering of the bacterial production host allows precise tuning of particle characteristics, including size, shape, and magnetic behavior, to meet specific application requirements. In this study, magnetosomes isolated from different Magnetospirillum gryphiswaldense mutant strains, each biomineralizing particles with distinct core diameters, were systematically evaluated as potential MPI tracers. Magnetic particle spectroscopy (MPS) was used to identify the most promising candidates based on their signal properties. These tracers were subsequently subjected to detailed signal analyses and phantom experiments to directly compare their imaging performance. Our findings demonstrate that genetically tailored magnetosomes can substantially improve MPI signal quality, underscoring their potential as next-generation tracers. This work provides a foundation for the rational design of optimized biogenic nanoparticles to advance preclinical and future clinical MPI applications. STATEMENT OF SIGNIFICANCE: Magnetic Particle Imaging (MPI) is a novel imaging technology with high sensitivity and real-time capabilities, making it highly promising for clinical applications such as blood flow monitoring and tumor detection. The performance of MPI strongly depends on the properties of the tracer materials used. However, producing high-quality tracers through conventional chemical synthesis remains challenging. In this study, we introduce an innovative biological approach by using genetically engineered magnetotactic bacteria to produce uniform magnetic nanoparticles, so-called magnetosomes. This strategy allows precise control of particle size, shape, and magnetic properties, resulting in tracers with superior performance. Our findings pave the way for the development of next-generation MPI tracers, advancing both fundamental research and potential clinical translation.

Temporomandibular disorder (TMD) is a common source of nondental orofacial pain. Exercise therapy is a recommended conservative treatment, yet inconsistent reporting of protocols limits reproducibility and clinical application. The primary objective of this scoping review was to determine the reporting of exercise therapy interventions in randomised controlled trials for TMD using the Template for Intervention Description and Replication (TIDieR) checklist. This scoping review assessed the completeness of exercise intervention reporting in randomised controlled trials (RCTs) for TMD using the TIDieR checklist. A comprehensive search across five databases and grey literature identified eligible RCTs. Data were extracted and analyzed using descriptive statistics and a Mann-Whitney U test. Seventy-five RCTs published between 1993 and 2024 were included. The mean TIDieR score was 7.98/12, with only 6.7% of studies reporting all checklist items. Frequently reported elements included intervention name, rationale and procedures. Tailoring, modifications, fidelity and adherence were underreported. No significant improvement in reporting quality was observed post-TIDieR publication. Reporting gaps persist in TMD exercise research, limiting reproducibility and clinical translation. Greater adherence to standardised reporting tools like TIDieR is needed to enhance transparency and evidence-based practice.

Molecular chaperones are an integral part of the proteostasis network of the cell that regulate client protein folding, substrate interactions, disaggregation, degradation, and intracellular trafficking, either independently or through coordinated action with co-chaperones. Among them, heat shock proteins have emerged as key players in cancer, largely owing to their ability to stabilize oncogenic proteins and support tumor initiation and malignant progression. Their expression is dysregulated in cancer cells and secreted into circulatory system as a consequence of oncogenic signaling pathways. Because of these properties, molecular chaperones, particularly heat shock proteins have gained traction as potential biomarkers for cancer detection, including in point-of-care diagnostic applications. However, as heat shock proteins are involved in basal cellular activities, their levels are perturbed in several other benign cellular conditions. This review highlights the multifaceted roles of molecular chaperones, with a focus on heat shock proteins, in cancer development and progression. It further discusses recent advances and perspectives on major heat shock proteins as biomarkers for cancer diagnosis, emphasizing their potential to improve diagnostic accuracy. Additionally, this review addresses current challenges and limitations associated with the diagnostic use of heat shock proteins, providing insights to guide future research and clinical translation.