Search Results (10,534)

Background/Objectives: Mitochondrial Oxidative Phosphorylation (OXPHOS) is a critical metabolic dependency in many cancers. Targeting OXPHOS through Leucine-Rich PPR Motif-Containing Protein (LRPPRC) degrader-mediated OXPHOS Complex Biogenesis Inhibition (OCBI) has demonstrated promising anti-tumor activity. However, rational combination strategies to enhance therapeutic efficacy remain undefined. This study aims to identify FDA-approved drugs that synergize with LRPPRC inhibition and elucidate the underlying mechanism. Methods: We conducted a high-throughput screen of 1376 FDA-approved compounds using LRPPRC isogenic cancer cell models to identify agents that synergize with LRPPRC degrader-based OCBI therapy. The synergistic effects of the candidate compound were validated in multiple cancer cell lines with either genetic ablation or pharmacological inhibition of LRPPRC. Mechanistic studies were performed to investigate the impact on OXPHOS gene expression from both nuclear and mitochondrial genomes. Results: The clinically approved multi-kinase inhibitor Dasatinib was identified as a robust synergistic candidate, exhibiting heightened sensitivity in cancer cells with either LRPPRC knockout or pharmacological inhibition. Mechanistically, Dasatinib selectively suppressed nuclear-encoded OXPHOS genes, whereas LRPPRC inhibition preferentially impaired mitochondrial DNA-encoded OXPHOS genes, resulting in a coordinated dual-genome blockade of OXPHOS. Conclusions: This study uncovers a previously unrecognized synergistic anti-tumor effect between LRPPRC inhibition and Dasatinib, mediated by complementary suppression of nuclear- and mitochondrial genome-encoded OXPHOS pathways. These findings provide a strong mechanistic and translational rationale for combination therapies targeting LRPPRC-high tumors. Full article

Background: The H1N1 influenza A virus evades host immunity through continuous antigenic drift, posing a significant challenge to broad-spectrum neutralizing antibody therapies. This study aims to systematically evaluate the neutralizing capacity of the broad-spectrum antibody C12H5 against H1N1 strains from different eras and identify key immune escape mutation sites. Methods: Three representative H1N1 virus strains from 2009, 2018, and 2023 were selected. An antigen–antibody binding prediction model based on the ESM-2 large language model was constructed by integrating 48,762 GISAID sequence data and deep mutation scanning data from the Bloom laboratory. Candidate escape sites were screened using SHAP (SHapley Additive exPlanations) value analysis. Mutant viruses were constructed via reverse genetics, and their neutralizing capacity and replication fitness were validated through hemagglutination inhibition assays, microneutralization assays, and viral growth kinetics analysis. Results: Machine learning scoring identified five potential escape sites, with K147 exhibiting the highest overall score (0.92). SHAP analysis revealed that the K147 site within the HA protein’s 130-loop region received the highest importance score (0.28), significantly surpassing other candidate sites. Experimental validation revealed that the K147N mutation reduced neutralizing potency against C12H5 by 8-fold (from 1:1024 to 1:128) and approximately 6-fold in microneutralization assays (from 8.3 log₂ to 5.7 log₂), while exhibiting a replication advantage in MDCK cells. Microneutralization assays further confirmed an approximately 6-fold reduction in neutralization sensitivity. Structural analysis indicated that K147 is located at the periphery of the HA receptor-binding domain, immediately adjacent to the receptor-binding site. Conclusions: K147N is identified as the critical mutation mediating C12H5 immune escape, and this mutation has emerged in 2023 circulating strains. This study provides important molecular targets and early warning mechanisms for broad-spectrum antibody optimization and influenza vaccine updates. Full article

The type II cadherin Cadherin-19 (CDH19) plays a crucial role in neural crest development. CDH19 regulates cell–cell junctions and migration by forming catenin–cytoskeleton complexes. Although anti-CDH19 monoclonal antibodies (mAbs) are used for specific applications such as Western blotting and immunohistochemistry (IHC), suitable anti-CDH19 mAbs for flow cytometry are limited. Therefore, developing mAbs that specifically recognize cell-surface-expressed CDH19 is essential for advancing both basic research and therapeutic strategies. Here, novel anti-human CDH19 mAbs (Ca₁₉Mabs) were created using flow cytometry-based high-throughput screening. One clone, Ca₁₉Mab-8 (IgG₁, κ), specifically recognized CDH19-overexpressed Chinese hamster ovary-K1 cells but did not bind to other 21 CDHs (including both type I and type II CDHs) in flow cytometry. Additionally, Ca₁₉Mab-8 recognized endogenous CDH19 in the human glioblastoma cell line LN229. The dissociation constant (K_D) of Ca₁₉Mab-8 for LN229/CDH19 was 9.0 × 10⁻⁹ M. Ca₁₉Mab-8 also detected endogenous CDH19 in Western blotting. Furthermore, Ca₁₉Mab-8 can detect CDH19 in IHC using human melanoma tissue. These findings suggest that Ca₁₉Mab-8 is a novel mAb that detects cell-surface-expressed CDH19 with high specificity and is suitable for various applications in basic research. Therefore, Ca₁₉Mab-8 has potential for clinical diagnosis and tumor therapy. Full article

Repetitive magnetic stimulation (rMS) and static magnetic stimulation (sMS) are currently employed as adjunctive therapies for specific neurological conditions. Despite substantial advances in cancer treatment, unfavorable prognoses and outcomes persist, especially for aggressive tumors, including glioblastoma and acute myeloid leukemia. The utilization of magnetic fields has shown antitumoral benefits in both in vitro and animal studies, suggesting its potential as an efficient non-invasive therapeutic approach; nevertheless, the precise mechanisms of action remain unclear. This scoping review intended to identify published research investigating the effects of sMS and rMS in in vitro and in vivo models to evaluate their impacts on morphological and molecular parameters. Four databases (PubMed, Embase, Web of Science, and Scopus) were assessed; the search strategy was limited to the past twenty-five years of data publication. Studies utilizing rMS or sMS as a treatment for conditions other than cancers, as well as those not considering these therapies as adjunctive therapy, were eliminated. Nine articles using rMS were included: three in vitro, two employing animal models, and the remaining four including both cellular and animal-based analyses. Sixteen studies using sMS were identified: twelve in vitro, three in vivo, and one with both models. The findings show that both rMS and sMS elicit a diverse array of biological responses in cancer cells, which are very variable and greatly influenced by tumor type, stimulation frequency, magnetic field intensity, exposure length, and experimental conditions. Full article

Background: Preterm birth is a leading cause of neonatal mortality and long-term disability worldwide. Injury in premature infants is demonstrated by disrupted organ development from inflammation, oxidative stress, hypoxia, and impaired vascular maturation. Current therapies largely provide supportive care and do not directly promote tissue regeneration. Mesenchymal stem cell (MSC)-based therapies have emerged as a potential strategy to enhance endogenous repair across organ systems commonly affected by prematurity. Results: Evidence indicates that MSCs exert therapeutic effects primarily through transient paracrine signaling rather than long-term engraftment. Following administration, MSCs release cytokines, growth factors, and extracellular vesicles that reduce inflammation, promote angiogenesis, and support tissue repair. In preclinical models of neonatal brain injury, MSC therapy has been associated with improved oligodendrocyte maturation and reduced white matter injury. Early clinical trials in neonatal encephalopathy demonstrate feasibility and short-term safety of both autologous and allogeneic cell products. However, studies remain limited by small sample sizes and short follow-up. Cell-free approaches using MSC-derived extracellular vesicles may offer similar biological benefits with potentially lower safety and regulatory concerns. Conclusions: MSC-based therapies represent a promising regenerative approach for complications of prematurity. Rigorous, large-scale trials with standardized protocols and long-term follow-up are necessary to clarify efficacy, optimize delivery strategies, and define safety in this vulnerable population. Full article

Background/Objectives: Research on the association between change from baseline in patient-reported outcomes (PROs) and overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) exists. This study evaluated the association between post-baseline PROs and OS in patients with advanced NSCLC who received first-line cemiplimab-based therapy. Methods: We evaluated PRO data from two phase III studies (EMPOWER-Lung 1 [NCT03088540] and EMPOWER-Lung 3 [NCT03409614]) using a Cox proportional hazards model. Twelve pre-specified PRO scales from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Quality of Life Questionnaire Lung Cancer 13 module were evaluated. Landmark analyses were conducted at 3, 6, 9, and 12 months. Time-dependent analyses using change from baseline PROs as a time-dependent covariate were conducted to evaluate the association of post-baseline PRO improvement with OS. Results: At the 3-month landmark, we observed a 56% reduction in the risk of death (HR = 0.44; 95% CI: 0.32–0.62; nominal p < 0.0001) among stable/improved vs. worsened/unobserved PROs for global health status (GHS)/quality of life (QoL). Results at the 6-, 9-, and 12-month landmarks of GHS/QoL were consistent with those at the 3-month landmark. Time-dependent analyses showed that every 10-point improvement in GHS/QoL was associated with a 31% reduction in the risk of death (HR = 0.69; 95% CI: 0.64–0.75; nominal p < 0.0001). Conclusions: In patients with advanced NSCLC who received first-line cemiplimab-based therapy, improvements in post-baseline PROs are associated with improved OS. These results may inform endpoint selection and interpretation of future clinical trials. Full article

Wilms tumor (WT) is the most common malignant renal tumor in childhood and represents one of the major success stories of pediatric oncology, with very good survival achieved through risk-adapted multimodal therapy. Nevertheless, a subset of patients—particularly those with diffuse anaplasia, blastemal-type tumors persisting after chemotherapy, or relapsed disease—continues to experience poor outcomes and significant long-term treatment-related morbidity. These challenges highlight the need for novel therapeutic strategies beyond conventional cytotoxic approaches. Growing evidence indicates that WT is characterized by a complex and distinctive tumor microenvironment (TME) shaped by its developmental origin and triphasic histology. Immune cell infiltration, inflammatory mediators, and immune checkpoint pathways interact differently with blastemal, epithelial, and stromal tumor components, generating heterogeneous immune surveillance and escape mechanisms. In particular, tumor-associated macrophages (TAMs), functionally impaired natural killer (NK) cells, and immunosuppressive stromal elements play a central role in shaping an immune milieu that may limit the efficacy of immune-based therapies. Although immunotherapy has changed the management of several adult malignancies and some pediatric cancers, its translation to WT has so far been limited, with modest results in unselected patient populations. Recent immunogenomic and proteogenomic studies, however, suggest the existence of biologically distinct WT subsets with different immune features and potential susceptibility to targeted immunotherapeutic approaches. This narrative review integrates pathological, immunological, and clinical perspectives to summarize current knowledge on the WT immune microenvironment, mechanisms of tumor immune evasion, and emerging immunotherapeutic strategies. By providing a unified framework, it aims at supporting a multidisciplinary approach for the rational development of future immune-based and combination therapies tailored to specific WT subgroups. Full article

Background/Objectives: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains associated with poor prognosis despite multimodal therapy. Metabolic reprogramming, particularly increased dependence on glutamine, supports GBM bioenergetic, biosynthetic, and redox demands. This study aimed to systematically identify glutamine-associated metabolic regulators with prognostic relevance and biological plausibility in GBM. Methods: Transcriptomic data from TCGA and GTEx were analyzed using GEPIA2, with survival validation performed using the CGGA. Functional pathway enrichment, protein expression assessment, protein–protein interaction network analysis, tumor microenvironment evaluation, epigenetic profiling, and single-cell RNA sequencing validation were integrated to contextualize candidate genes. Pharmacogenomic correlation analysis and structure-based molecular docking were applied as supportive validation layers. Results: Ceruloplasmin (CP), Solute Carrier Family 25 Member 13 (SLC25A13), and Solute Carrier Family 38 Member 2 (SLC38A2) were selectively dysregulated and associated with poor clinical outcomes in GBM. CP was linked to redox regulation and stress-adaptive survival programs, SLC25A13 to mitochondrial metabolite exchange and glutamine-coupled nucleotide biosynthesis, and SLC38A2 to glutamine uptake, nutrient sensing, and mTORC1-MYC-associated growth signaling. Conclusions: CP, SLC25A13, and SLC38A2 emerge as clinically relevant glutamine-associated metabolic regulators in GBM, linking redox regulation, mitochondrial metabolite exchange, and glutamine-driven growth signaling. These findings highlight transport- and exchange-centered metabolic nodes as potential biomarkers and candidates for future metabolic targeting in GBM. Full article

Bloodstream infection (BSI) is a serious clinical condition associated with high morbidity and mortality, requiring rapid identification of causative agents and timely antimicrobial susceptibility testing (AST). This study evaluated accelerated bacterial identification from positive blood culture samples using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) combined with two rapid processing approaches: a serum separation tube-based centrifugation method (SST method) and shortened cultivation on solid media. Rapid identification was followed by accelerated AST, performed either from a bacterial cell pellet (SST method) and from early-grown bacterial biomass (shortened cultivation protocol). The results were compared with those obtained using routine laboratory procedures. A total of 270 positive blood culture samples were analyzed, with 135 samples processed by each protocol. Both approaches achieved an identification success rate of 93.33%. Rapid AST using the SST method showed error rates of 0.51% minor errors, 0.57% major errors, and 0.23% very major errors, with an overall agreement of 98.69%. The shortened cultivation protocol demonstrated lower error rates (0.46% minor errors and 0.23% major errors) and an overall agreement of 99.31%. These findings confirm that MALDI-TOF MS enables reliable early identification of BSI pathogens and rapid AST, supporting timely optimization of antimicrobial therapy and early detection of multidrug-resistant strains. Full article

Background/Objectives: Despite recent advances in breast cancer diagnostics, therapies and personalized medicine through genetic profiling, effective treatment of aggressive subtypes, particularly triple-negative breast cancer (TNBC), remains a considerable clinical challenge. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that influence tumor progression and are detectable extracellularly in biofluids, where they are typically protected within extracellular vesicles (e.g., exosomes) or associated with RNA-binding proteins and lipoprotein complexes. This review integrates current evidence on oncogenic and tumor-suppressive extracellular miRNAs in breast cancer, with emphasis on subtype-specific functions and potential clinical relevance as liquid-biopsy biomarkers and therapeutic targets. Methods: A PubMed-based literature review (January 2000–February 2026) was conducted using search terms combining “breast cancer” with “miRNA/microRNA” and “circulating/plasma/serum/exosomal/extracellular vesicle.” Studies were prioritized if they provided validated targets/mechanisms and/or human clinical evidence for diagnostic, prognostic, or predictive utility; discrepant findings were evaluated in a subtype-aware framework. Findings were organized into functional categories (e.g., EMT/metastasis, cell-cycle/DNA damage, immune modulation, and hormone/growth factor signaling). Clinical and translational studies evaluating circulating miRNAs for diagnosis, prognosis, treatment response, and toxicity prediction were synthesized, together with key pre-analytical and analytical variables that affect reproducibility. Results: Across mechanistic and clinical studies, miR-21 and miR-155 recur as prominent oncogenic miRNAs, whereas miR-205 is frequently reported as a tumor-suppressive miRNA that is reduced in breast cancer and in circulation in several cohorts. Panels combining these miRNAs show promise for sensitive and specific breast cancer diagnostics. Additionally, several miRNAs show context- or subtype-dependent effects, with opposing activities reported between TNBC and estrogen receptor (ER)-positive disease (e.g., miR-17-92, miR-425, miR-181 family members, miR-31, and miR-24). Conclusions: Circulating miRNAs represent a promising class of minimally invasive biomarkers and potential therapeutic targets; however, translation is constrained by biological context dependence and by pre-analytical and analytical variability. Standardized protocols and rigorously validated, subtype-aware biomarker panels will be essential for clinical implementation and for enabling miRNA-informed precision oncology in breast cancer. Full article

Leukopenia remains a major clinical challenge associated with infectious diseases, oncological therapies, autoimmune disorders, and metabolic and iatrogenic conditions. Insufficient leukopoiesis not only increases susceptibility to infections but also limits the intensity and continuity of anticancer and immunosuppressive treatments. Targeted stimulation of leukopoiesis therefore represents a critical therapeutic strategy in modern biomedicine. This narrative review summarizes pharmacological and biotechnological approaches to leukopoiesis stimulation based on an analysis of peer-reviewed literature from major biomedical databases. Emphasis was placed on molecular mechanisms of action, clinical positioning, and translational potential of leukopoiesis-modulating agents. Current leukopoiesis-stimulating strategies encompass cytokine-based therapies, bone marrow-derived peptides, thymic and microbial immunomodulators, nucleic acid-based agents, plant-derived compounds, and chemically synthesized small molecules. Classical colony-stimulating factors remain the cornerstone of clinical practice; however, their limitations, including adverse effects and restricted spectrum of action, have driven the development of alternative approaches. Emerging strategies increasingly target specific regulatory nodes of hematopoiesis, including bone marrow stromal interactions, transcription factor signaling, chemokine receptor pathways, and immune cell differentiation programs. Advances in the understanding of leukopoiesis regulation have expanded therapeutic opportunities beyond conventional growth factor administration. Pharmacological and biotechnological targeting of leukopoiesis holds promise for improving clinical outcomes in patients with leukopenia of diverse etiologies. Future progress in this field will depend on the integration of mechanistic insights with clinical evidence to enable more selective, effective, and safer leukopoiesis-stimulating therapies. Full article

Neural progenitor cell (NPC) transplantation is a promising strategy for spinal cord injury repair, as graft-derived neurons can integrate into host circuitry and promote functional recovery. While the brain-regional and dorsoventral identities of NPCs are known to influence graft composition and performance, the importance of axial (rostrocaudal) identity, specifically whether NPCs must be matched to the spinal level of injury, remains poorly understood. To address this, we compared outcomes following transplantation of NPCs isolated from the anterior embryonic spinal cord (A-NPCs) versus the posterior spinal cord (P-NPCs) in a mouse model of C5 cervical dorsal column injury. Following transplantation, NPCs retained their intrinsic molecular axial identities; P-NPC grafts maintained significantly higher expression of the lumbar-associated gene HoxC10 and possessed a higher proportion of Chx10-high V2a neurons compared to A-NPCs. Despite these maintained molecular differences, A-NPC and P-NPC grafts were indistinguishable in neuronal and glial density, axon outgrowth, and their ability to support host axon regeneration, including the corticospinal tract. Long-term behavioral testing and retrograde transsynaptic tracing revealed no significant differences between groups in the recovery of skilled pellet reaching, grip strength, or synaptic integration with host cervical motor circuitry. These findings demonstrate that although transplanted NPCs retain their molecular axial identity in the adult injured environment, this identity is not a primary determinant of anatomical integration or functional outcome. Our findings suggest a degree of plasticity in graft-host interactions and indicate that strict segment-matching is not essential for the efficacy of NPC-based therapies in spinal cord injury. Full article

The engineering of theranostic nanoparticles, which integrate diagnostics and therapy in a single administration, enables targeted drug delivery and disease visualization. In cancer theranostics, gadolinium-based nanoparticles are valuable tools for noninvasive magnetic resonance imaging (MRI) and provide high-resolution images of the tumor. When MRI is combined with other imaging modalities, complementary therapeutic information is obtained for more accurate identification of tumor characteristics and precise guidance of anticancer drug delivery. Among the many possible modalities combined with MRI, photoacoustic imaging (PAI) is a candidate that enables sensitive in vivo detection of tumors. We have already succeeded in synthesizing biocompatible gelatin-coated gadolinium oxide nanoparticles with a controlled size by adjusting the timing of gelatin addition, which were a highly efficient contrast agent for MR and PA dual imaging. Herein, we conjugated a clinically used anticancer drug (doxorubicin, DOX) to size-defined and biocompatible gadolinium oxide nanoparticles which are novel theranostic probes. Succinylated gelatin enabled the electrostatic conjugation of DOX with gadolinium oxide nanoparticles, and the release of DOX was controlled through the enzymatic degradation of gelatin by matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9), which are highly expressed in cancer cells. The released DOX efficiently inhibited the growth of HeLa cells in vitro and the growth of the inoculated tumor tissues in vivo. The dual-modality MRI and PAI capabilities provide anatomical information that assists in the localization and targeting of theranostic probes. Full article

Stem cell heterogeneity represents a critical yet underexplored variable in laser-assisted regenerative strategies. While photobiomodulation has been shown to influence mesenchymal stem cell (MSC) behavior, it remains unclear whether stem cell maturation status modulates responsiveness to Er,Cr:YSGG irradiation. This study investigated the differential response of magnetically separated STRO-1⁺ and STRO-1⁻ SHED subpopulations to low-power Er,Cr:YSGG laser stimulation (0.10 W and 0.25 W), focusing on viability, extracellular matrix production, and lineage commitment. STRO-1⁺ cells comprised 13.4% ± 1.2% of the total Stem Cells from Human Exfoliated Deciduous teeth (SHED) population. Laser exposure did not impair metabolic activity in either subpopulation. Collagen synthesis demonstrated a power- and time-dependent increase, with maximal enhancement observed in STRO-1⁺ cells at 0.25 W after 7 days. Laser irradiation selectively promoted osteogenic differentiation, as evidenced by increased alkaline phosphatase (ALP) expression at 0.10 W and enhanced mineral deposition, while chondrogenic potential remained unaffected and adipogenesis was reduced following 0.10 W exposure. These findings suggest that ALP expression is temporally and power-dependently modulated during osteogenic progression. Overall, Er,Cr:YSGG photobiomodulation does not uniformly affect heterogeneous SHED populations but modulates lineage allocation and extracellular matrix deposition in a maturation- and power-dependent manner. Integrating stem cell subpopulation selection with laser-based bioactivation may represent a strategy to refine regenerative endodontic and biomaterial-guided therapies. Full article

The liver plays a fundamental role in maintaining homeostasis thanks to the numerous functions performed by this organ. Non-inherited metabolic liver diseases, inherited metabolic liver diseases, and liver cancers are pathological conditions affecting liver function and that can lead to its failure. To date, for end-stage liver diseases—where the remaining hepatic tissue is no longer capable of regenerating sufficiently rapidly—or for metabolic diseases involving the liver, liver transplantation remains the standard and ideal therapeutic approach. However, this is limited by donor availability, surgical costs, and the tangible risk of autoimmune rejection, which may occur at varying intervals post-surgery. Furthermore, for the duration of their lives, transplant recipients must undergo systemic immunosuppressive treatment to prevent rejection; this is associated with high costs and severe side effects, including infections and secondary malignancies. In this review, we discuss these pathologies and how recent cell-based therapies and/or gene therapy approaches have emerged as promising alternatives that can provide either temporary restoration of hepatic function or long-term benefits, potentially reducing the global burden of liver disorders. Full article