Abstract: Background/Objectives: Severe asthma in routine practice often involves long-standing disease, multimorbidity, and prior biologic failure, settings underrepresented in pivotal tezepelumab trials. This study evaluated 52 week real world effectiveness and safety of tezepelumab in a highly comorbid, predominantly T2 high, biologic experienced severe asthma cohort from the Canary Islands. Methods: TEZNERIFE is a multicenter, retrospective phase IV study including consecutive adolescents and adults with GINA Step 5 severe uncontrolled asthma treated with tezepelumab 210 mg every 4 weeks for 12 months. Clinical outcomes, lung function, type 2 biomarkers, upper airway symptoms, and Biologics Asthma Response Score (BARS) were assessed at baseline, 26 weeks, and 52 weeks. Results: Fifty six patients (mean age 53.5 years, 71% female, mean asthma duration 30 years, 84% T2 high; 71% with ≥1 prior biologic) were analyzed. ACT improved from 11.5±3.7 to 15.9±4.7 at 26 weeks and 17.5±4.7 at 52 weeks (both p<0.0001), while annualized exacerbations declined from 2.79±2.0 to 0.50±0.72 and 0.51±0.89 (both p<0.0001). Maintenance oral corticosteroid dose fell from 10.2±8.3 to 6.9±2.4 mg/day at 52 weeks (p=0.014). FEV1% predicted increased from 69.3±19.2% to 75.3±17.7% and 76.2±20.6% (p=0.004 and p=0.001), and blood eosinophils decreased from 234±231 to 146±120 and 147±110 cells/µL (p=0.001 and p=0.013). At one year, 18.9% and 67.9% were classified as good and intermediate responders by BARS; 13.2% were insufficient responders. Two patients discontinued due to non serious adverse events while no treatment related serious events occurred. Conclusions: In this difficult to treat, multimorbid, biologic experienced population, tezepelumab achieved sustained improvements in asthma control, exacerbations, lung function, eosinophilic inflammation, and corticosteroid exposure over 52 weeks, supporting upstream alarmin inhibition as a versatile strategy in complex severe asthma.

Abstract: We evaluated global radiotherapy practices in the management of early-stage (AJCC/UICC 8th edition stages I-II) glottic cancer (ESGC). A cross-sectional online survey was conducted in March 2025 across centers worldwide. Data was collected on clinical practices, including staging, CT simulation, target volumes delineation, organs-at-risk contouring, radiotherapy techniques, dose and fractionation schedules, treatment delivery techniques, and image guidance practices. A total of 181 responses were received, primarily from Asia (41.4%) and Europe (24.3%). Most respondents were from non-academic public centers (44.2%), with multidisciplinary team involvement reported by 84.5%. Head and neck CT scan was the most used staging modality (80.1%). Intensity-Modulated Radiation Therapy was the most common planning technique (82.9%). Hypofractionated radiotherapy schedules predominated for T1 (84%) and T2 (72.4%) disease. T1a was typically treated with whole-larynx target volume (72.4%). Use of ipsilateral involved vocal cord irradiation varied by geographical region (p = 0.015), being most common in North America (44.8%) and Europe (38.6%). Accelerated fractionation for T2 also differed significantly (p < 0.001), with the highest use reported in North America (41.4%). Daily Cone-Beam Computed Tomography was acquired by (58.2%). 70% of respondents expressed interest in the results of a future phase III randomized trial comparing stereotactic body radiation therapy to conventional radiotherapy. Significant global variations in radiotherapy practices for ESGC were observed, likely reflecting disparities in access and differences in institutional protocols. The development and implementation of standardized, evidence-based global guidelines are essential to harmonize care, minimize toxicity, and improve outcomes for patients with ESGC.

Abstract: Early cancer detection has historically relied on episodic, population-based screening strategies interpreted against fixed thresholds. Although effective in selected contexts, such approaches detect disease primarily after structural or biochemical abnormalities become overt. Advances in genomics, liquid biopsy, and metabolomics now permit a conceptual transition from static screening toward longitudinal, biologically calibrated surveillance. This review proposes an integrated early-detection architecture grounded in four complementary dimensions of tumorigenesis: inherited susceptibility, somatic field evolution, molecular residual disease, and functional metabolic remodeling. Germline variants establish life-course risk and recalibrate surveillance intensity. Somatic mutational signatures and field cancerization describe spatial conditioning of tissues long before overt malignancy. Circulating tumor DNA (ctDNA) provides temporal resolution by tracking clonal persistence after therapy. Extending this framework, emerging evidence from microbiome and metabolomic studies supports the hypothesis that sustained alterations in volatile organic compound (VOC) profiles may reflect early tumor–microbiome ecosystem shifts. Although a comprehensive wearable multi-gas detection device is not yet clinically available, current technological advances render continuous “volatomics” biologically plausible and conceptually aligned with trajectory-based monitoring. Rather than advocating a single transformative assay, this manuscript argues for convergence: longitudinal biomarker baselines, germline priors, tumor-informed molecular templates, ctDNA dynamics, and prospective metabolic sensing integrated within a calibrated decision system. Such a platform would function not as a replacement for established diagnostic tools, but as a stratified triage architecture capable of identifying sustained biological deviation warranting further evaluation. Early detection, in this reframed paradigm, becomes a dynamic process of recognizing evolving biological drift rather than a binary event triggered by threshold crossing.

Abstract: AbstractBruceine A is a major quassinoid isolated from the seeds of Brucea javanica and has been reported to exhibit significant anticancer and antiplasmodial activities. Structural modification of Bruceine-A through semisynthesis is a rational approach to improve its biological potential. This study aimed to design and evaluate semisynthesized pathways for Bruceine-A derivatives and to elucidate the reaction mechanism. Two semisynthesis routes were evaluated: (i) a protection–deprotection strategy involving tert-butyldimethylsilyl chloride (TBDMS-Cl), and (ii) a direct acylation approach. Due to limitations in material availability and reaction complexity, the second pathway was selected. Direct acylation of Bruceine A in N,N-dimethylformamide (DMF) using imidazole as a base catalyst successfully yielded 3-O-chlorobenzoylbruceine (P1). Structural elucidation was performed using UV, IR, ^1H-NMR, ^13C-NMR, and LC–MS. The results demonstrate that direct acylation at the C-3 hydroxyl group is an efficient and selective strategy for the semisynthesis of Bruceine A derivatives.Keywords: Bruceine A, quassinoid, semisynthesis, acylation, Brucea javanica, 3-O-chlorobenzoylbruceine

Abstract: Oculomics represents a paradigm shift in medicine, redefining the eye as a non-invasive window into systemic health rather than merely a target of disease. This emerging interdisciplinary field leverages high-resolution ocular imaging—including fundus photography, optical coherence tomography (OCT), and OCT angiography—along with molecular analysis of ocular biofluids to identify biomarkers of cardiovascular, metabolic, neurodegenerative, renal, and environmental diseases. Grounded in the retina’s shared embryological, neurovascular, and metabolic pathways with the brain and systemic vasculature, oculomics enables the detection of subclinical pathological processes often years before overt clinical manifestations. The integration of artificial intelligence, particularly deep learning, has been instrumental in decoding complex, high-dimensional ocular data, transforming routine eye examinations into scalable platforms for predictive risk stratification and personalized medicine. Unlike prior reviews focused on technological implementation or clinical integration, this work provides a mechanistic, disease-centric synthesis that maps quantitative retinal and tear-fluid biomarkers to underlying systemic pathophysiology, offering a granular blueprint for future translational research. This review synthesizes the biological rationale, key technologies, and disease-specific evidence underpinning oculomics, while critically examining its translational framework—termed “Healthcare from the Eye.” We also address persistent challenges related to standardization, clinical validation, ethical governance, and health system integration. As these barriers are addressed, oculomics is poised to reposition ophthalmology at the forefront of preventive and precision medicine, making routine eye care a gateway to early systemic health assessment and intervention.

Abstract: The block-and-lock strategy aims to achieve a functional cure for human immunodeficiency virus type 1 (HIV-1) infection by enforcing durable, drug-independent silencing of proviral transcription. Several latency-promoting agents have been described that effectively limit viral reactivation in vitro or in animal models. However, most approaches induce only partial or reversible transcriptional repression and have not yet been translated into safe and effective clinical interventions. This review summarizes the molecular mechanisms underlying block-and-lock strategies and critically evaluates the limitations of current candidate compounds. We highlight recent advances in understanding HIV-1 integration site selection, focusing on the roles of lens epithelium-derived growth factor p75 (LEDGF/p75) and cleavage and polyadenylation specificity factor subunit 6 (CPSF6) in directing proviral integration toward gene-dense, transcriptionally active chromatin. Pharmacological disruption of the LEDGF/p75–integrase interaction by LEDGF/p75 inhibitors (LEDGINs) redirects proviral integration toward less transcriptionally active genomic regions that are more resistant to reactivation. Recent tandem knockout studies, however, demonstrate that CPSF6 plays a dominant role in guiding HIV-1 integration toward gene-dense, transcriptionally active chromatin. LEDGIN treatment has been linked to the preferential targeting of proviruses to heterochromatin-rich regions within the nuclear interior. By contrast, CPSF6 knockout redirects integration toward peripheral heterochromatin, especially lamina-associated domains (LADs), genomic regions typically exhibiting stronger and more stable transcriptional repression than interior heterochromatin. These findings suggest that therapeutic modulation of CPSF6 may exert a more profound and durable effect on proviral silencing within a block-and-lock framework. Nevertheless, complete CPSF6 ablation is associated with severe cellular toxicity. The challenges associated with CPSF6-related adverse effects and potential strategies to overcome these limitations are discussed.

Abstract: Diffuse large B-cell lymphoma (DLBCL) is one of the most frequent subtypes of non-Hodgkin lymphoma (NHL). This study is a proof of concept computer vision exercise to support the feasibility of predicting the prognosis of DLBCL using only hematoxylin and eosin (H&E) histological images and deep learning. A conventional series of DLBCL of 114 cases was split into 2 prognostic groups according to the overall survival curve. The curve fitting and slope analysis showed a point of inflection at 2 years, which differentiated patients of “Dead < 2 years” with aggressive (b1 = -0.024), and “Others” with moderate clinical evolution (b1 = -0.003). Twenty different convolutional neural networks (CNNs) were used, and explainable artificial intelligence (XAI) was applied to identify the areas of the images that the network used for classification. The final model based on DarkNet-19 predicted prognosis groups with high performance (test set accuracy = 96.26%). The other performance parameters were precision (94.46%), recall (95.02%), false positive rate (3.07%), specificity (96.93%), and F1 score (94.74%). XAI, including grad-CAM, occlusion sensitivity, and image-LIME, confirmed that the CNN focused on the correct areas. Hybrid partitioning to prevent information leakage with patient-based analysis and image classification between DLBCL and 44 cases of reactive lymphoid tissue were also successfully performed. Correlation with the clinicopathological characteristics found that the Dead < 2 years group was correlated with stage III-IV, International Prognostic Index (IPI) High + High/intermediate, progressive disease, non-GCB cell-of-origin, CD10-, BCL2+, and Epstein-Barr virus (EBER)+. Analysis of the microenvironment, immune checkpoint, cell cycle, and germinal center markers showed that Dead < 2 years had higher IL10, PD-L1, and CD163, and lower E2F1 protein expressions. No differences were found for Ki67, CSF1R, CASP8, TNFAIP8, LMO2, MYC, MDM2, CDK6, and TP53 markers. In conclusion, the overall survival of DLBCL can be predicted using H&E histological images and deep learning using 2 years point (similar to POD24). This trained CNN could be used as a pretrained model for transfer learning in the future.

Abstract:

Background: Unanticipated difficult airways remain a leading cause of anesthesia-related morbidity and mortality, with traditional bedside predictors demonstrating limited sensitivity. Point-of-Care Ultrasound (POCUS) has emerged as a non-invasive adjunct offering real-time visualization and quantitative measurement of airway anatomy. This narrative review, structured according to the Scale for the Assessment of Narrative Review Articles (SANRA), synthesizes current evidence on Point-of-Care Ultrasound (POCUS) as an adjunct for airway evaluation. We explore the sonoanatomy of the upper airway, the utility of ultrasound in predicting difficult laryngoscopy and intubation, its critical role in emergency front-of-neck access (FONA), and the verification of endotracheal tube placement. Furthermore, we discuss the integration of Artificial Intelligence (AI) in image interpretation and the necessity of standardized training curricula. Methods: We systematically searched PubMed/MEDLINE, Scopus, and Web of Science for English-language peer-reviewed studies addressing sonographic airway assessment, including sonoanatomy, prediction of difficult laryngoscopy/intubation, guidance for emergency front-of-neck access (FONA) and endotracheal tube confirmation. Results: POCUS enhances visualization of critical anatomical structures, improves predictive accuracy when combined with clinical assessment, and provides real-time guidance during emergency procedures. Integration of Artificial Intelligence shows promise for automated image interpretation. Conclusions: Airway ultrasound represents a paradigm shift toward personalized, safer airway management. However, standardized training protocols and validation in diverse clinical settings remain essential. Future research should focus on developing evidence-based algorithms integrating POCUS into airway management guidelines.

Abstract: Precise quantitative determination of Vascular Endothelial Growth Factor (VEGF) in human plasma is critical for pharmacodynamic (PD) evaluation of anti-VEGF therapeutics. In this study, we developed and optimized two immunoassay platforms, including the enzyme-linked immunosorbent assay (ELISA) and the Meso Scale Discovery (MSD), for estimating VEGF. A direct sandwich ELISA was validated to quantify pharmacodynamic biomarker VEGF in human plasma using the Human VEGF Quantikine Kit, demonstrating a quantification range of 62.5–2000.0 pg/mL and a sensitivity of 47.5 pg/mL. In parallel, a sandwich electrochemiluminescence (ECL) assay was developed using the V-PLEX Plus Human VEGF Kit on the MSD platform, achieving a lower quantification range of 7.7–562.0 pg/mL. Comparative analysis revealed that MSD ECL detection with Sulfo Tag labeling outperformed traditional colorimetric ELISA in terms of signal amplification and dynamic range, making it a valuable tool for PD biomarker analysis. Findings underscore the importance of early platform selection to ensure robust, fit-for-purpose biomarker quantification for clinical pharmacology studies and regulatory submissions.

Abstract: (1) Background. Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on LPA-induced activation of ERK1/2 and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) Methods. LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Results. Amitriptyline potentiated LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway, including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and CREB. Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as reversal of astrocyte stellation, accumulation of stress fibers, and phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) Conclusion. These results demostrate that in astroglial cells amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho-ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug.

Abstract: Although oral leukoplakia (OL) is recognized as a precancerous lesion, only a proportion of cases undergo malignant transformation (7,2 % to 9.5%). That's why recently, increasing attention has been directed toward molecular biomarkers that may better reflect the biological behaviour of OL Infiltration density of T and B lymphocytes, macrophages, plasma cells were assessed semi-quantitatively using a 4-point scale adapted from Nankivel study. CD9 antigen was assessed in epithelial and immune cells by counting them in three 400x fields. CD138 and CD68 biomarkers were associated with significantly elevated expression across both clinical types of OL where dysplasia was diagnosed. The increase in infiltration density with CD3 and CD20 labelled lymphocytes was statistically reliably confirmed only in non-homogeneous OL with dysplasia. CD9, as a protein reflecting the exosome compartments, revealed the interaction between the epithelium and immune cells. A moderate, statistically significant positive correlation was found only in leukoplakia with dysplasia between CD9+ immune cell levels and the number of epithelial layers expressing this antigen. Assessment of combinations of CD3, CD9, CD20, CD68, and CD138 biomarker expression, cons idering clinical type of leukoplakia, particularly non-homogeneous, appears to improve the accuracy of determining the risk of malignancy in individuals with oral dysplasia.

Abstract: Background and Objectives: Metaplastic breast carcinoma (MBC) is a rare, aggressive malignancy often resistant to conventional chemotherapy and characterized by a triple-negative phenotype. While immune checkpoint inhibition shows promise, the prognostic significance and distribution of programmed death-ligand 1 (PD-L1) expression within the heterogeneous architecture of MBC remain poorly understood. This study aimed to evaluate PD-L1 expression and the density of tumor-infiltrating lymphocytes (TILs) to clarify their roles in patient stratification and overall survival (OS). Materials and Methods: We retrospectively analyzed 48 MBC cases diagnosed between 2010 and 2025. PD-L1 expression was quantified using the Combined Positive Score (CPS) with the 22C3 antibody clone across diverse histological components. The density of stromal TILs density was assessed following internationally standardized guidelines. Clinical outcomes and clinicopathological parameters, including metastasis, lymphovascular invasion (LVI), and histological subtype were correlated with biomarker status using Kaplan-Meier survival analysis and Cox proportional hazards regression models. Results: PD-L1 positivity (CPS ≥1) was identified in 72.9/% of cases, one of the highest rates documented in literature. Notably, an inverse relationship was observed with PD-L1 negative tumors exhibited significantly higher rates of distant metastasis (46.2% vs. 17.1%; p=0.039). Multivariate analysis confirmed that low density of TILs (HR=9.66; p=0.016), metastasis (HR=4.40; p=0.023), and the presence of LVI (HR=3.84; p=0.047) were strong independent predictors of mortality. While PD-L1 status alone did not directly dictate overall survival, mean overall survival was markedly reduced in the low TILs cohort (32.2 months) compared to the high TILs group (114.2 months). Conclusion: The high prevalence of PD-L1 expression supports routine screening for immunotherapy eligibility in MBC. Our findings suggest that PD-L1 negative cases represent a high-risk biological subset driven by alternative immune evasion mechanisms. Integrating TILs density with conventional pathological parameters provides a more robust prognostic framework, enabling personalized therapeutic strategies for this challenging malignancy.

Abstract: Background/Objectives: Evidence exists suggesting that the pathophysiology of IBS is multifaceted, involving mucosal inflammation, visceral hypersensitivity, microbial dysbiosis, and alterations in intestinal permeability. In our study, we found that the zonulin protein plays a role in IBS, and that pyroptosis can be triggered by inflammatory responses that lead to increased intestinal permeability and impaired intestinal permeability.Methods: Forty-four patients over 18 years of age who did not exhibit alarm symptoms, did not have systemic diseases affecting bowel movements, were not using medications that could affect bowel movements, and were not pregnant, and forty-four healthy individuals who signed the voluntary consent form were included in the study on a voluntary basis after undergoing colonoscopy and receiving a diagnosis of IBS according to the ROME-IV criteria. Levels of IL-1β, Nirp3, Gasdermin-D, and Zonulin Protein-A were examined in the patients, and serum levels were measured according to the normal reference range determined by our laboratory.Results: When the patient and control groups were compared, IL-1β levels were found to be statistically significantly higher in the patient group (p=0.000). NLRP3 levels were found to be statistically significantly higher in the patient group (p=0.000). The mean Gasdermin-d level was found to be statistically significantly higher in the patient group (p=0.009). The mean Zonulin Protein-A level was found to be statistically significantly higher in the patient group (p=0.001).Conclusion: In the etiopathogenesis of IBS, zonulin protein a and pyroptosis-related marker levels (Nlrp3, Il-1b, Gasdermin-D); The fact that it was detected significantly higher in patients with ibs compared to healthy controls supports our predictions that pyroptosis can be induced by inflammatory responses that may cause increased intestinal permeability and intestinal permeability, in which zonulin protein plays a role in ibs.

Abstract: The investigation of biomarkers capable of identifying subgroups of psychiatric patients based on a combination of clinical and neurobiological features, such as white matter hyperintensities (WMH), will enable more accurate medical practice, with a better prediction of clinical presentation, progression, and response to treatment. The aim of this study was to investigate whether patients with acute psychiatric symptoms could be grouped according to clinical and neurobiological features. A k-means cluster analysis of 90 acute psychiatric inpatients, aged 45 to 75 years, who met criteria for schizophrenia, bipolar disorder, and major depressive disorder was performed. Multidimensional clinical and neuroimagological data were included in the analysis. Validity of the clusters was tested by re-clustering the sample and comparing the silhouette coefficient. The cluster analysis extracted three clinical phenotypes that can be identified based on the burden of WMH. A “vascular-cognitive” phenotype (cluster 1, n=13), a “low vascular-psychiatric” phenotype (cluster 2, n=58), and a “vascular-depressive/apathy” phenotype (cluster 3, n=19). The silhouette coefficient was higher in the clusters including the WMH variable, reflecting a structuring effect on the clusters. The cluster analysis extracted subgroups of subjects that can be distinguished by WMH burden, cognitive performance, and psychiatric symptoms.

Abstract: Measles remains a major global public health challenge as declining vaccination coverage fuels outbreaks worldwide. Although pneumonia is the most recognized respiratory complication, spontaneous air leak syndrome—including pneumomediastinum, subcutaneous emphysema, and pneumoperitoneum—is rarely documented. We report the case of a 9-year-old previously healthy girl with no documented measles–rubella vaccination who presented with fever, maculopapular exanthem, Koplik spots, and persistent cough. Measles was confirmed by both immunoglobulin M enzyme-linked immunosorbent assay and real-time reverse transcription polymerase chain reaction. She developed sudden cervicothoracic swelling and chest pain. Chest radiography revealed pneumomediastinum and subcutaneous emphysema; computed tomography confirmed extensive air leak including left pneumothorax and pneumoperitoneum. Flexible bronchoscopy and upper gastrointestinal endoscopy excluded structural airway and esophageal injury. Laboratory evaluation revealed elevated hepatic transaminases, gamma-glutamyl transferase, lactate dehydrogenase, and D-dimer. Conservative management with high-flow supplemental oxygen and clinical surveillance led to progressive resolution. The patient was discharged on hospital day three, asymptomatic and breathing room air. This case highlights the spectrum of air leak complications in measles and supports conservative management in hemodynamically stable pediatric patients when structural injury has been excluded.

Abstract: The phenotypic plasticity of epithelial cells along the epithelial-mesenchymal (E-M) axis, or epithelial-mesenchymal transition (EMT), is a critical aspect of tumour progression and therapeutic resistance. During EMT, epithelial cells gradually acquire mesenchymal traits, facilitating vital functions in embryogenesis, wound healing, fibrosis, and tumour metastasis. This review article investigates the interplay between hyperglycaemia-induced metabolic stress and EMT in the context of therapeutic resistance. The study examines a complex, multifaceted network of molecular mechanisms regulating EMT, including specialised transcription factors and signalling pathways as well as growth factors, integrins, and matrix metalloproteinases in various epithelial carcinomas. Emerging findings have demonstrated the existence of EMT hybrid states along the continuum, possessing heightened metastatic potential and distinctive metabolic signatures that play critical roles in the development of therapeutic resistance in cancer cells. Hyperglycaemia has been particularly highlighted for its potential to promote EMT-driven therapeutic resistance through various interconnected mechanisms. Elevated glucose levels induce the increased production of reactive oxygen species (ROS), activation of EMT-promoting transcription factors, and a metabolic shift towards glycolysis. This hyperglycaemic stress involves upregulation of glucose transporters and glycolytic enzymes creating feed-forward loops that support drug efflux mechanisms and help maintain the mesenchymal phenotype. Clinical data also indicate that hyperglycaemia in OSCC patients is associated with more advanced tumour stages, more ex-tended hospital stays, less effective treatments, and higher rates of local recurrence and distant metastasis. Overall, these insights emphasise the urgent need for a more comprehensive understanding of the underlying mechanisms linking hyperglycaemia and EMT to the treatment resistance axis and to explore glucose control strategies that can be incorporated into cancer treatments to overcome anti-cancer therapy resistance effectively.

Abstract: Immune-mediated tissue injury is typically conceptualized as a consequence of aberrant immune activation; however, spatial patterns of lesion formation and selective tissue vulnerability across diseases suggest that immune activity alone may not determine where damage becomes established. We propose a generalizable systems framework in which regional metabolic preconditioning, defined by local perfusion dynamics, oxygen availability, and bioenergetic resilience, modulates the threshold for immune-mediated injury. In this model, tissue susceptibility emerges from the interaction between (1) immune activation intensity and (2) region-specific metabolic state. Reduced perfusion and relative hypoxia stabilize hypoxia-inducible signaling pathways, alter endothelial integrity, reprogram cellular metabolism, and amplify inflammatory responsiveness. These processes do not initiate autoimmunity but reshape the energetic and vascular landscape in which immune mechanisms operate, thereby governing spatial lesion topology and progression. We formalize this interaction as a threshold-modulation framework in which tissue injury probability is a function of both immune effector load and metabolic resilience. Applied to multiple sclerosis as a model system, this perspective integrates cerebral hypoperfusion, mitochondrial dysfunction, blood-brain barrier instability, and compartmentalized inflammation into a unified explanatory structure. The framework generates falsifiable predictions regarding perfusion-lesion coupling, metabolic biomarkers of susceptibility, and cross-disease parallels in immune-driven pathology. By positioning metabolic state as a dynamic modifier of immune injury thresholds, this model shifts emphasis from single-axis causation toward systems-level interaction, offering a conceptual template for understanding spatial selectivity and progression in immune-mediated diseases.

Abstract: Background and Objectives: Bladder cancer (BCa) is characterized by high rates of re-currence and progression, underscoring the need for reliable non-invasive biomarkers. Circular RNAs (circRNAs) are covalently closed non-coding RNAs generated by back-splicing and are stable in biological fluids, including urine. Increasing evidence im-plies circRNAs in BCa pathogenesis; however, identification of clinically relevant circRNAs remains labor-intensive. This study aimed to streamline circRNA selection and identify functionally relevant urinary circRNAs in BCa. Methods: Using a database-screening ap-proach, we identified circRNAs with high predicted affinity to miR-101-3p, a tu-mor-suppressive microRNA in BCa. Candidate circRNAs were prioritized based on: (i) strong miR-101-3p binding potential; (ii) derivation from genes involved in BCa tumor-igenesis; and (iii) origination from exonic or long non-coding RNA sequences. The po-tential contribution of Argonaute-2 (Ago2) binding sites to circRNA–miRNA complex sta-bility was also evaluated. Expression levels were assessed in urine samples and BCa cell lines, and functional relevance was examined using molecular and cellular assays. Results: circCIAO1(5) and circMALAT1 fulfilled all prioritization criteria and exhibited distinct Ago2-binding site profiles. Both circRNAs were upregulated in urine from BCa patients and in aggressive BCa cell lines and showed differential expression between remission and recurrent disease. CircCIAO1(5) demonstrated higher-affinity binding to miR-101-3p, while RNA immunoprecipitation confirmed interactions of both circRNAs with miR-101-3p and Ago2. Functional assays revealed enhanced proliferation, motility, and invasion upon circRNA expression, consistent with miR-101-3p sequestration and derepression of miR-101-3p target oncogene-EZH2. Conclusions: circCIAO1(5) and circMALAT1 represent promising urinary biomarkers for BCa, illustrating the value of bioinformatics-guided circRNA discovery and significance of circRNA-mediated regulatory mechanisms in BCa biology.

Abstract: Lipoblastomas are rare, rapidly growing benign tumors rising from embryonic white fatty cells that continue to proliferate in the postnatal period. We presented a case of a toddler with an undifferentiated myxoid neoplasm with features of a minimally differentiated lipoblastoma. Our patient was an 18-month-old female with a painless solid tumefaction in the middle third of the right leg. Histopathologically, the nodular tumor mass consisted of lipobastic cells embedded in a myxoid stroma. Immunohistochemistry showed strong diffuse positivity for vimentin, S100, CD34, CD56, NSE and rare Ki67+ cells. FOXO1 polyploidy was detected in 30% of cells by FISH. Using target RNA sequencing, we detected a fusion gene, CHCHD7-PLAG1, in the tumor sample. Sequence analysis showed that the first exons of CHCHD7 were fused to either exon 2 or exon 3 of PLAG1. Our case demonstrates that due to the histomorphologic overlaps, the molecular diagnostics is essential for confirmation of lipoblastomas.

Abstract: Background/Objectives: Vaccination against respiratory viruses—such as respiratory syncytial virus (RSV), pneumococcal disease, influenza, and COVID-19—may reduce the risk of adverse outcomes in older adults with cardiovascular disease. This study conducted a scoping review of the effects of respiratory vaccines in older adults with cardiovascular disease. Methods: We included studies evaluating adults aged ≥60 years with cardiovascular disease who received different types of respiratory vaccines. Eligible designs comprised clinical trials, observational cohort studies, and other relevant studies. Editorials, commentaries, and non-original publications were excluded. A comprehensive and targeted literature search was conducted in PubMed, Scopus, EMBASE, and Web of Science from database inception through January 2026. Results: A total of 26 studies were included, encompassing 1,782,787 adults aged ≥60 years with cardiovascular disease who received various respiratory vaccines. RSV vaccines were associated with a lower incidence of cardiorespiratory hospitalization and stroke among vaccinated individuals. Pneumococcal vaccines showed that sequential dual vaccination strategies were associated with a lower risk of cardiovascular events. Influenza vaccination was associated with improved cardiovascular outcomes, lower mortality, and reduced adverse events. COVID-19 vaccines were associated with reductions in mortality and hospitalizations. These benefits are particularly relevant in an older population with a high burden of comorbidities; therefore, complete vaccination schedules, including booster doses, should be considered a central strategy for prevention and comprehensive management in this high-risk group. Conclusions: Vaccination against respiratory viruses in older adults with cardiovascular disease demonstrates an overall favorable/acceptable profile of efficacy and safety, with reductions in mortality, hospitalizations, and cardiovascular events, without a significant increase in serious adverse events.