Search Results (27,222)

Background: Pharmacological treatment under conditions of slow fibrinolysis/thrombolysis requires the targeted delivery of plasminogen-activating activity. Echogenic liposomal formulations (regular TELIP) of single-chain tissue plasminogen activator (sctPA), while possessing high affinity to fibrin, contain free/loosely bound sctPA. We hypothesized that removal of free sctPA, which competes with liposomes and plasmin for fibrin, enhances unique features of the TELIP. Methods: Optimized and regular TELIP were assessed for the distribution of active sctPA (loosely bound, tightly bound, encapsulated), stability, binding to fibrin, initiating fibrinolysis in vitro and ex vivo using a battery of biochemical methods. Results: One milligram of the regular TELIP consists of 2.0–5.0 × 10⁹ echogenic liposomes (700–900 nm diameter). Non-specifically bound sctPA readily dissociates at the physiological ionic strength and pH. While up to 60% of sctPA in the regular TELIP is loosely bound with 6–15% encapsulated, and the rest is tightly bound to the liposomes; in the optimized TELIP, more than 80% of active sctPA is tightly bound with up to 40% of encapsulated. The latter is protected from high-molecular-weight ligands and could be released by an ultrasound pulse. Optimized TELIP shows low competition with plasmin for fibrin and effectively supports fibrinolysis in vitro and ex vivo. The optimized TELIP with maximal load of sctPA 3% (w/w) retains integrity at 37 °C for 5 h in vitro and up to 2 h ex vivo. Conclusions: The optimized TELIP is stable in vitro and ex vivo, does not interfere with fibrinolysis and retains a high level of encapsulated sctPA delivered precisely to the thrombus/fibrin clot. Full article

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as the most transformative cellular immunotherapy modality, with its evolutionary trajectory intrinsically coupled to advances in immune receptor structure–function paradigms. Recent technological breakthroughs have yielded unprecedented mechanistic insights into immune receptors. Cryo-electron microscopy, single-cell omics, and structural biology have revealed the molecular architecture and functional dynamics of key receptors, including T-cell receptors (TCRs) and B-cell receptors (BCRs). This comprehensive review systematically integrates the latest discoveries in immune receptor structure–function relationships, emphasizing the mechanistic underpinnings of receptor diversity generation, signal transduction networks, and their direct translational impact on CAR-T therapeutic optimization. We critically examine the innovative design principles governing fourth-generation CAR-T cells, delineate breakthrough strategies for overcoming solid tumor immunoresistance, and analyze the synergistic potential of CAR-T and TCR-T technological convergence. Particular attention is devoted to elucidating how fundamental immune receptor research can be harnessed to address the tripartite challenges of safety, efficacy, and persistence that currently constrain CAR-T clinical applications. This review establishes a mechanistic framework for developing next-generation CAR-T technologies grounded in immune receptor biology and provides strategic insights for accelerating cellular immunotherapy clinical translation. Full article

Sepsis, which affects 49 million people yearly, killing 11 million of them, is known to induce severe liver dysfunction. It is characterized by extensive metabolic reprogramming, resulting in acute metabolic loss of function and maladaptive repair that can prime the organ for fibrosis rather than functional regeneration. To understand how intercellular communication dictates these outcomes, we performed cell type-specific bulk RNA-sequencing on hepatocytes (HEP), hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), and CD45⁺ leukocytes (CD45) from mice following polymicrobial sepsis. Cell-cell communication analyses using CellChat and NicheNet revealed a clear reorganization of the hepatic environment. While HSCs remain largely quiescent during homeostasis, after sepsis, they become the liver’s central signaling hub and broadcast potent fibrogenic and chemotactic signals (e.g., Ccl7) to surrounding cells. This actively suppresses hepatocyte metabolic functions, promotes leukocyte infiltration, and may further initiate early fibrogenic priming. Our findings highlight HSCs as regulators during septic acute liver injury, revealing communication nodes that could be targeted to constrain fibrosis responses and promote normal functions and repair. Full article

Avian metapneumovirus (aMPV) is a major respiratory pathogen of poultry with a significant economic impact; however, its epidemiology at the wildlife–poultry interface remains poorly understood, particularly within Afro–Eurasian migratory systems. This cross-sectional study (December 2024–April 2026) investigated aMPV occurrence in wild birds across eleven Egyptian governorates representing key ecological zones along major migratory flyways. A total of 1280 samples were collected from 800 wild birds representing migratory waterfowl and synanthropic species, including 800 oropharyngeal swabs tested by real-time RT-qPCR for aMPV subtypes A and B and 480 serum samples analyzed using indirect ELISA. aMPV RNA was detected in 28/800 samples (3.5%), with all positives identified as subtype B and confined to the Nile Delta, Middle Egypt, and Canal Region. In contrast, serological analysis revealed a high seroprevalence of 58.3% (280/480), indicating widespread prior exposure with significant spatial and species-level variation (p < 0.05). The marked disparity between low molecular detection and high seroprevalence supports transient infection with cumulative exposure. The exclusive detection of subtype B may reflect epidemiological connectivity between poultry and wild bird populations within shared ecological interfaces; however, the directionality of transmission and the possibility of independent wildlife maintenance could not be determined within the scope of the present cross-sectional study. Future studies incorporating whole-genome sequencing, longitudinal surveillance, and broader flyway-scale sampling are needed to resolve transmission pathways and distinguish field strains from potential vaccine-derived viruses within wildlife–poultry interfaces. Full article

A 7-week study was conducted to investigate the effects of replacing fish meal (FM) with Spirulina residue meal (SPRM) on the growth, feed utilization, carcass composition, antioxidant ability, liver and intestinal histology of juvenile rainbow trout (Oncorhynchus mykiss) (initial body weight 5.36 ± 0.04 g). Four isonitrogenous (42%) and isolipidic (16%) diets were formulated to replace FM protein with SPRM at 0 (SPRM0), 10% (SPRM10), 20% (SPRM20) and 30% (SPRM30), respectively. Results showed that growth, feed utilization, carcass amino acid profile, serum biochemical indices, antioxidant ability, intestinal and liver histology were not significantly affected by dietary SPRM levels. Whole-body lipid content decreased as dietary SPRM replacement levels increased, and fish fed diet SPRM30 had lower lipid content than that fish fed diet SPRM0 (p < 0.05). Fish fed diet SPRM30 had higher C16:1n-7, C20:3n-6, total saturated fatty acid (SFA) and total fatty acid (TFA) contents in muscle than those fed other diets (p < 0.05), while these fatty acids had no change when FM was substituted with 10% and 20% SPRM (p > 0.05). The muscle C22:6n-3 (DHA) content decreased, but C18:3n-6 and n-6/n-3 polyunsaturated fatty acid (PUFA) ratio increased with increasing SPRM levels, and fish fed diet SPRM30 had significantly lower DHA content and higher n-6/n-3 ratio than the group fed SPRM0 (p < 0.05). The C22:1n-9, C18:2n-6c, C20:4n-6, total n-6 PUFA, and monounsaturated fatty acid (MUFA) content in muscle observed in SPRM30 were similar to the SPRM0 group (p > 0.05), but higher than the SPRM10 and SPRM20 groups (p < 0.05). In conclusion, 30% of FM protein could be replaced by SPRM in diets of juvenile rainbow trout without having a significant negative effect on growth, feed efficiency, antioxidant ability, and structure of liver and intestine, but could reduce DHA content, increase n-6 PUFA and n-6/n-3 PUFA ratio in muscle. Full article

Introduction: Accurate detection and characterization of intracardiac masses remain a major challenge in cardiovascular imaging due to overlapping morphological features between tumors, thrombi, and vegetations, as well as the inherent limitations of echocardiography, including operator dependency and variable image quality. Although echocardiography is the first-line imaging modality for evaluating cardiac masses, diagnostic uncertainty frequently necessitates additional multimodality imaging. Artificial intelligence (AI), including machine learning and deep learning approaches, has emerged as a promising strategy to improve image interpretation, automate feature extraction, and enhance diagnostic consistency. Objective: This narrative review aims to examine current advances in AI-enhanced echocardiography for cardiac tumor detection, with a particular focus on detection, segmentation, classification, multimodal integration, and clinical translation. Methods: A narrative literature review was conducted using PubMed, Scopus, and Google Scholar databases. Relevant English-language studies published between 2016 and 2026 were identified using keywords including “artificial intelligence”, “machine learning”, “deep learning”, “echocardiography”, “cardiac tumors”, “intracardiac masses”, “multimodal imaging”, and “ultrasomics”. Original studies, reviews, and methodological papers related to AI-assisted cardiovascular imaging were evaluated. Discussion: Current evidence suggests that AI-driven techniques, including radiomics (ultrasomics), convolutional neural networks, and multimodal learning frameworks, can improve the detection, segmentation, and classification of intracardiac masses. Experimental studies have reported high diagnostic performance, with some deep learning models achieving diagnostic accuracies exceeding 95% under controlled conditions. AI-assisted systems may also reduce interobserver variability and improve workflow efficiency. Multimodal AI approaches integrating echocardiography with cardiac magnetic resonance imaging, computed tomography, electrocardiography, and clinical data appear particularly promising for improving diagnostic discrimination. However, current models remain limited by small and imbalanced datasets, insufficient external validation, data heterogeneity, and limited generalizability across institutions and imaging protocols. Additional barriers to clinical implementation include annotation variability, limited interpretability of deep learning models, and regulatory considerations. Conclusions: AI-enhanced echocardiography has substantial potential to improve the detection and characterization of intracardiac masses by augmenting diagnostic consistency and supporting clinical decision-making. Nevertheless, current evidence remains largely based on retrospective and experimental studies. Future progress will depend on large multicenter collaborations, standardized imaging datasets, explainable AI frameworks, and prospective clinical validation to enable safe and effective integration into routine cardiovascular practice. Full article

Background/Objectives: Radiogenomics integrates quantitative imaging features with genomic and molecular data to better characterize tumor biology and support precision oncology. While extensively investigated in solid tumors, its application to hematologic malignancies remains relatively unexplored despite the widespread use of advanced imaging in lymphoma and multiple myeloma. Methods: A systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, and Web of Science were searched up to December 2025 for studies investigating radiogenomic associations in hematologic malignancies. Study quality was assessed using PROBAST and METRICS. Two reviewers independently screened all records and performed data extraction through consensus. Results: Twelve studies were included, covering multiple myeloma and various lymphoma subtypes (aggressive B-cell lymphoma, classical Hodgkin lymphoma, and primary CNS lymphoma). Imaging modalities included PET/CT, MRI and CT. Across studies, radiomic and imaging-derived features were associated with cytogenetic abnormalities, gene expression profiles, and circulating tumor DNA metrics. In multiple myeloma, MRI and CT-based radiomics showed promising ability to predict high-risk cytogenetic abnormalities. In lymphoma, PET-derived volumetric and dissemination features correlated with molecular risk profiles and tumor microenvironment characteristics. Several studies demonstrated improved prognostic performance when imaging features were combined with genomic or clinical variables. Conclusions: Radiogenomic approaches in hematologic malignancies show promising potential for non-invasive risk stratification and improved prognostic assessment. However, current evidence remains limited by small cohorts, heterogeneous methodologies, and a lack of external validation. Prospective multicenter studies and standardized imaging–genomic pipelines will be essential to enable clinical translation. Full article

Lameness associated with bacterial chondronecrosis with osteomyelitis (BCO) continues to be an important topic of great interest to global poultry production. Caused by bacterial infection of susceptible necrotic bone tissue, the disease severely affects animal health, welfare, and productivity, leading to significant economic losses annually. In recent years, the Kazakhstan poultry industry has enjoyed significant investment and strong growth, with goals of self-sufficiency within the decade. However, there remains a significant knowledge gap in poultry research in the nation, especially regarding the topic of BCO lameness. As such, this study aims to provide a preliminary evaluation of BCO lesion prevalence in different geographical regions of the country―namely Abai, Almaty, and Akmola. In each region, about 200 broilers from local poultry farms were procured, humanely euthanized, and necropsied to evaluate prevalence of femoral and tibial lesions commonly associated with BCO lameness. On average, most broilers had no damage to femoral head (78.17%) followed by femoral head separation (FHS, 11.94%), while the tibial head saw ubiquitous degrees of damage ranging from severe (71.42%) to observable (23.06%). These findings signify potential underlying issues connected to BCO lameness that will necessitate early management and intervention measures to prevent future spread of the disease. Full article

Background: Diffuse Large B-cell Lymphoma (DLBCL) is a biologically heterogeneous subtype of non-Hodgkin’s lymphoma (NHL), accounting for 30–40% of cases worldwide. Despite the incorporation of rituximab into standard chemo-immunotherapy regimen, approximately one-third of patients present with relapsed or refractory disease, implicating the need for improved prognostic markers and therapeutic targets. Gene expression profiling successfully classified DLBCL into Germinal Center B-cell-like (GCB) and non-GCB subtypes, which differ in genetic alterations, response to therapy, and clinical outcome. While intrinsic tumor biology has been extensively studied, the contribution of the tumor microenvironment (TME) to disease progression and therapeutic resistance still remains incompletely understood. Methods: In this study, we investigated the mutational landscape of stromal-related genes in DLBCL and evaluated their impact on gene expression, downstream signaling pathways, and tumor progression. Results: A total of 176 DLBCL patients were screened, of which 113 were enrolled based on availability of complete clinical data. The cohort demonstrated male predominance (male:female ratio: 2.1:1), advanced disease stage in 72.6% of patients, and elevated serum lactate dehydrogenase levels in 57.5%. Based on immunohistochemistry, 43.4% cases were classified as GCB-DLBCL and 56.6% as non-GCB DLBCL. Although the International Prognostic Index (IPI) retained prognostic significance for event-free survival (EFS) and overall survival (OS), considerable heterogeneity was observed within similar risk groups. Whole-exome sequencing (WES) uncovered recurrent somatic mutations in key oncogenic and epigenetic regulators, including TNFAIP3, NFIB, NOTCH1, TSC2, EZH2, EP300, KMT2D, and B2M, with subtype-specific distribution. Pathway enrichment analysis implicated role of Notch, Wnt, mTOR, JAK-STAT, TGF-β, and antigen-presentation pathways. Comprehensive WES analysis identified multiple novel mutations in genes associated with the stromal/extracellular matrix with distinct patterns in GCB and non-GCB DLBCL, accompanied by concordant alterations in gene expression profiles, suggesting functional relevance within the TME. Functional validation through primary cell culture demonstrated significantly elevated Th2 (IL-4, IL-6, IL-10) and Th17 (IL-17) cytokines in co-cultures containing both neoplastic cells and stromal components, underscoring the role of TME in DLBCL progression. Conclusions: Taken together, this study provides novel insights into stromal mutational signatures and cytokine-mediated tumor–stroma interactions, offering potential prognostic biomarkers and therapeutic targets for the improved management of DLBCL. Full article

Background/Objectives: Liposarcoma represents a heterogeneous group of mesenchymal malignancies with distinct molecular profiles and clinical behaviors. While localized disease is managed with surgical resection, advanced or metastatic liposarcoma poses a significant therapeutic challenge due to limited response to traditional cytotoxic chemotherapy. This review summarizes current evidence-based systemic therapies and highlights recent advances in subtype-driven treatment strategies. Methods: We review key clinical trials supporting the use of anthracycline regimens, trabectedin, eribulin, and nuclear export inhibition with selinexor, as well as emerging targeted approaches directed at MDM2 and CDK4 amplification. In addition, we discuss the evolving role of immunotherapy, including checkpoint inhibitors and engineered T-cell receptor therapies targeting cancer–testis antigens. Results: Integrating molecular biology with therapeutic development, we emphasize the importance of histologic and genomic classification in guiding treatment selection and clinical trial design. Conclusion: Continued progress in biomarker-driven strategies and rational combination therapies is expected to further refine personalized treatment approaches and improve outcomes for patients with advanced liposarcoma. Full article

Background and Clinical Significance: Cutaneous paraneoplastic phenomena are infrequently characterised in colorectal cancer (CRC), and chronic pruriginous inflammatory eruptions in particular have received limited attention. In older adults, persistent treatment-resistant dermatoses of unclear aetiology may represent overlooked extraintestinal diagnostic clues to occult malignancy, including potentially curable CRC. Faecal immunochemical testing (FIT) for occult bleeding is a low-cost, non-invasive tool whose role outside conventional alarm-symptom triage remains underexplored. Case presentation: A 72-year-old woman presented for outpatient evaluation with several months of pruriginous, pustular, and crusted symmetric eruption involving the dorsal aspects of the limbs, refractory to standard dermatologic treatment, and without gastrointestinal symptoms. A non-invasive systemic stool-based work-up demonstrated detectable faecal haemoglobin (iFOBT), mildly elevated faecal calprotectin (51.6 mg/kg, ULN 50 mg/kg), markedly elevated faecal alpha-1-antitrypsin (631 µg/mL; 2.3× ULN), and predominance of Escherichia coli on stool culture. Colonoscopy revealed a locally advanced rectal adenocarcinoma; staging classified the lesion as cT3N1M0. The patient received long-course neoadjuvant chemoradiotherapy (50 Gy, concurrent capecitabine) followed by low anterior resection with total mesorectal excision and pathological complete response (ypT0N0, R0), and adjuvant capecitabine. The cutaneous eruption resolved progressively in parallel with antineoplastic therapy without specific dermatologic intervention. The patient remains in remission at over 36 months. Conclusions: Persistent, unexplained, treatment-resistant pruriginous/pustular cutaneous eruptions may, in selected patients, coincide with an underlying malignancy, including colorectal cancer, and should prompt careful individualised clinical assessment, including review of age-appropriate colorectal cancer screening status. This single case raises the hypothesis that quantitative faecal immunochemical testing (FIT) may be prospectively evaluated as a low-cost, non-invasive triage tool in carefully selected patients aged ≥50 years with persistent dermatoses of unclear aetiology, even in the absence of gastrointestinal symptoms. Positive FIT results should be managed according to established local colorectal referral pathways. NICE diagnostics guidance DG56 supports FIT use in symptomatic adults with suspected lower gastrointestinal pathology; however, any extension of FIT to extraintestinal presentations remains investigational and requires formal validation through prospective studies assessing diagnostic yield, cost-effectiveness, and stage distribution. Full article

Natural products are the fundamentals of drug discovery due to their exceptional structural diversity and biological activity’s evolutionary optimization. The review provides a critical and integrative analysis of natural products in pharmaceutical chemistry, highlighting their significance for current biomedicine and pharmacotherapy. The review is organized around a system that connects structure, function, and translation, focusing on structural analysis, scaffold design, and mechanistic understanding in major disease-relevant therapeutic areas. Investigations on representative compounds like paclitaxel, artemisinin, and curcumin are presented to explain the way molecular architecture regulates pharmacological activity, drug selectivity, and clinical performance. The review evaluates significant medicinal chemistry strategies, including semisynthetic modification, prodrug design, and scaffold optimization, and their crucial roles in enhancing potency, pharmacokinetics, and safety. We critically examine the latest advancements in drug delivery technologies, particularly those based on nanotechnology and carrier-free methods, regarding their translational potential and regulatory concern. Current challenges pertaining to pharmacokinetics and ADMET properties, as well as the standardization of analysis, are also examined, emphasizing their impact on reproducibility in research. Researchers investigate the role and limitations of emerging fields such as genome mining, synthetic biology, and network pharmacology in enhancing discovery pipelines. Thus, this review integrates chemical, pharmacological, and translational approaches and suggests an effective strategy to overcome challenges in the development of natural products as the next generation of precision medicine therapeutic agents. Full article

Obesity is a major global health challenge characterized by chronic low-grade inflammation, oxidative stress, and an increased risk of cardiometabolic disorders. Although sex-related differences in inflammatory and redox biomarkers have been reported in obese populations, the molecular mechanisms underlying this heterogeneity remain incompletely understood. In this study, we applied a proteomics-based approach to investigate urinary extracellular vesicles from 45 obese individuals (BMI 30–40 kg/m²; age 50–70 years) in order to identify molecular signatures associated with metabolic dysregulation. Shotgun proteomics analysis performed by nanoLC–MS/MS enabled the identification of 3822 proteins. Hierarchical clustering of proteomic profiles revealed two distinct molecular groups, predominantly enriched in males (Group I) and females (Group II). Label-free quantitative analysis identified 466 differentially abundant proteins between the two clusters. Functional enrichment analysis highlighted pathways associated with immune response, metabolic regulation, and redox homeostasis, including glycolysis/gluconeogenesis, lysosome activity, leukocyte transendothelial migration, and glutathione, cysteine and methionine metabolism. Notably, proteins related to ferroptosis were enriched, suggesting the involvement of iron-dependent oxidative cell death mechanisms in the metabolic imbalance observed in a subset of subjects. Furthermore, the non-enzymatic glycosylation of urinary proteins was significantly higher in Group I compared with Group II (p = 0.0002), indicating increased formation of advanced glycation products in individuals with a more pronounced pro-oxidant state. Preliminary follow-up data suggested a higher incidence of pathological events, including cardiovascular complications, among individuals belonging to Group I. Overall, these findings demonstrate that urinary proteomic profiling can identify distinct molecular phenotypes among obese individuals and highlight oxidative stress, ferroptosis, and protein glycation as potential determinants of metabolic vulnerability, supporting the use of non-invasive proteomic approaches for improved risk stratification in obesity. Full article

Bronchopulmonary dysplasia (BPD) remains a major complication of extreme prematurity, driven in part by persistent inflammation. Interleukin (IL)-1–mediated signaling plays a central role in sustaining lung injury, making IL-1 blockade a potential therapeutic target. Evidence on the use of anakinra, a recombinant IL-1 receptor antagonist, in neonatal BPD is still limited. We report the case of a female preterm infant (28⁺² weeks’ gestation, birth weight 800 g, −1.41 zs) affected by BPD requiring prolonged respiratory support. Due to persistent respiratory failure despite standard therapies, off-label treatment with subcutaneous anakinra (5 mg/kg twice daily) was initiated at 150 days of life. Clinical respiratory parameters and exploratory salivary inflammatory biomarkers (IL-6 and soluble urokinase plasminogen activator receptor, suPAR) were longitudinally monitored. Following anakinra initiation, the patient showed a gradual improvement in respiratory parameters, with reduction in oxygen requirement, mean airway pressure, and improved gas exchange. Respiratory support was gradually de-escalated from nasal intermittent positive pressure ventilation to continuous positive airway pressure and subsequently to high-flow nasal cannula. Salivary suPAR levels demonstrated a decreasing trend, while IL-6 showed transient fluctuations, partly associated with intercurrent infections. Treatment was generally well tolerated during the observation period. The infant was discharged on minimal respiratory support, with continued improvement during follow-up. This case suggests a possible role of IL-1 blockade in the modulation of persistent inflammation in BPD with a refractory clinical course, although the observed clinical course may also reflect the natural evolution of the disease. Longitudinal salivary biomarkers may represent a feasible, exploratory, non-invasive approach to describe inflammatory dynamics over time. Larger prospective studies are needed to evaluate the efficacy, safety, and optimal treatment protocols of anakinra. Full article