Search Results (6,407)

Mitochondria-targeting metal complexes (MTMCs) are a mechanistically distinct class of metallopharmaceuticals. Unlike first-generation platinum drugs that form nuclear DNA adducts, MTMCs exploit organelle-specific vulnerabilities such as hyperpolarised mitochondrial membrane potential (ΔΨm), elevated reactive oxygen species (ROS), limited mitochondrial DNA (mtDNA) repair capacity, and redox-dependent enzymes such as thioredoxin reductase (TrxR). We systematically searched PubMed, Web of Science, Scopus, and Google Scholar databases for studies published between 2016 and 2026, applying predefined inclusion criteria that included subcellular localization evidence and functional bioenergetic endpoints. The search identified 147 studies covering Pt(II/IV), Ru(II/III), Au(I/III), Ir(III), Os(II), Re(I), and V(IV/V) complexes and metal–organic framework nanoplatforms. Mechanistic evidence converges on four intramitochondrial target categories: inhibition of ETC (Electron Transport Chain) Complexes I/III with consequent ATP depletion; ROS overproduction, coupled with glutathione and TrxR depletion; outer mitochondrial membrane permeabilization and intrinsic apoptotic cascade activation; and mtDNA damage within a compartment limited to base excision repair. Multi-modal cell death—the co-occurrence of apoptosis, ferroptosis, necroptosis, and autophagic cell death—was a recurrent finding across the reviewed studies. This review thoroughly surveys the latest trends in MTMC drug design (metals, ligand structures, and mechanisms of action) and summarises analytical techniques for speciation, pharmacokinetics, safe monitoring, and resistance, while critically analysing translational barriers and clinical failures. To address the field’s inconsistent terminology, we introduce an explicit localization evidence hierarchy that distinguishes mitochondria-targeting complexes (through quantitative ICP-MS fractionation or co-localization with defined Pearson/Manders coefficients) from simply mitochondria-localising or mitochondria-perturbing agents, and we apply it throughout. We also point out that the idea of selectivity being purely driven by membrane voltage (ΔΨm) and thermodynamics is constrained by membrane and protein binding, as well as the transmembrane pH gradient, kinetic limitations, and demonstrated heterogeneity of cancer-cell membrane potential, and, as such, the functional mitochondrial effects must not be equated with mitochondrial accumulation. Since elemental quantification cannot distinguish intact complex from protein adducts and decomposition products, speciation-aware pharmacokinetics emerges as a prerequisite for a credible exposure–response interpretation. The translational progress will depend less on new chemotypes than on this analytical and pharmacokinetic rigour, together with organelle-level safety monitoring and biomarker-guided patient selection. Full article

Background: Chronic low back pain (CLBP) is the leading cause of years lived with disability globally, affecting over 600 million individuals. Intervertebral disc degeneration (IVDD) is a principal structural contributor, yet conventional treatments, including pharmacotherapy, physical therapy, and surgical intervention, do not reverse the underlying degenerative pathology. Regenerative medicine has introduced a spectrum of biological therapies for IVDD, including cell-based mesenchymal stromal cell (MSC) therapy, platelet-derived products such as platelet-rich plasma (PRP) and platelet lysate, extracellular vesicle-based approaches using MSC-derived extracellular vesicles (EVs), and secretome-based therapies using MSC-derived secretomes. However, these approaches have largely been studied in isolation, without a unified framework to compare their respective advantages and limitations in CLBP secondary to IVDD. Accordingly, this narrative review aims to provide an integrated and comparative evaluation of these regenerative strategies within a single translational and clinical context. Methods: For this narrative review, PubMed, Scopus, and Web of Science were searched from January 2000 to January 2026 using terms combining regenerative modalities with intervertebral disc degeneration, and chronic low back pain. Randomized controlled trials (RCTs), prospective cohort studies, systematic reviews, and preclinical studies with translational relevance were included. Results: Intradiscal MSC therapy has demonstrated safety across multiple phase I–III trials, but two recent landmark RCTs (RESPINE and the Mesoblast phase III trial) failed to meet primary efficacy endpoints, highlighting the gap between preclinical promise and clinical outcomes. PRP has the largest clinical evidence base, with level II evidence supporting short- to medium-term pain relief for discogenic pain, although standardization remains a critical barrier. Platelet lysate, MSC-derived EVs, and MSC-derived secretomes show compelling preclinical data, including extracellular matrix restoration, anti-inflammatory modulation, and attenuation of nucleus pulposus cell apoptosis, but remain at early translational stages for spinal applications, with no completed RCTs. The hostile disc microenvironment (avascular, hypoxic, acidic, and nutrient-poor) poses unique challenges for all regenerative modalities, differing fundamentally from other musculoskeletal applications. Conclusions: The studies included in this narrative review suggest that no single regenerative modality has yet shown consistent and unequivocal efficacy for CLBP secondary to IVDD across clinical trials. Cell-free approaches offer manufacturing, scalability, and safety advantages over cell-based therapies, but lack clinical validation. Future progress requires standardized preparation protocols, disc-specific delivery systems, patient phenotyping strategies, and rigorously designed comparative clinical trials. This narrative review provides a framework for researchers and clinicians to evaluate these therapies in context rather than isolation. Full article

Background: Endometriosis and lipedema are chronic female-predominant disorders characterized by persistent pain that is frequently disproportionate to anatomical lesion burden. Although traditionally interpreted within distinct lesion-centered frameworks, both conditions exhibit striking clinical and epidemiological parallels, including hormonally modulated symptom dynamics, overlap with central pain syndromes, weak correlation between structural disease severity and pain intensity, and symptom clustering during reproductive transitions such as puberty, pregnancy, and menopause. Methods: This study aims to synthesize clinical, molecular, neuroimmune, and endocrine evidence on the interrelationship between endometriosis and lipedema, and to propose a hypothesis-generating neuroimmune framework linking both conditions. This integrative narrative review conducted a non-systematic literature search in PubMed/MEDLINE, Scopus, and Web of Science, focusing on mechanisms related to chronic pain, mast cell biology, TRPV1 signaling, CGRP-mediated neurogenic inflammation, intracrine steroidogenesis, and peripheral and central sensitization. Results: The review identifies convergent biological characteristics between the two diseases, including mast cell activation, macrophage polarization, endothelial dysfunction, fibrosis, angiogenesis, intracrine estrogen metabolism, and persistent inflammatory signaling. In endometriosis, direct evidence demonstrates increased sensory innervation, nerve growth factor expression, TRPV1 sensitization, CGRP-positive fibers, and mast cell-nerve interactions. In lipedema, convergent upstream mechanisms, including mast cell infiltration, elevated histamine levels, adipose tissue inflammation, and local estrogen activation, support the plausibility of a functionally analogous neuroimmune organization, despite incomplete direct neural characterization. In this context, the mast cell-TRPV1-CGRP axis is proposed as a biologically plausible framework, directly supported in endometriosis and currently hypothetical in lipedema, connecting peripheral sensitization, neurogenic inflammation, hormonal chronodependence, and central nociceptive amplification. The model further conceptualizes pain crises as transient events of instability within a sensitized neuroimmune network and proposes mechanistic phenotypes that integrate gastrointestinal, inflammatory, central, and hormonal triggers. Conclusion: Endometriosis and lipedema may represent topographically distinct manifestations of a shared neuroimmune process operating within hormone-sensitive tissues. Although the evidentiary basis remains asymmetric, with stronger mechanistic support in endometriosis than in lipedema, this framework provides a biologically plausible and experimentally testable model integrating endocrine, immune, neural, and vascular contributors to chronic pain amplification. This perspective supports coordinated translational investigation across reproductive biology, endocrinology, and pain medicine and may contribute to future mechanism-based stratification and therapeutic development. This work is hypothesis-generating and is not intended to establish causality or to provide clinical recommendations; all proposed mechanistic and therapeutic inferences require prospective experimental validation. Full article

(1) Background: Reactive oxygen species (ROS) act as physiological signaling mediators but contribute to oxidative damage, cellular dysfunction, and age-related disease when redox homeostasis fails. Forkhead box O4 (FOXO4) has emerged as a redox-sensitive regulator linking stress adaptation, antioxidant defense, and cellular senescence. This structured narrative review critically evaluates which redox- and aging-related conclusions are supported directly for FOXO4 and which remain inferred from other FOXO isoforms. (2) Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to May 2026; Google Scholar was used only for supplementary citation tracking and did not contribute a separate platform-level count. Of 420 records, 300 remained after deduplication, 110 full texts were assessed, and 89 publications were retained. FOXO4-related evidence was classified as directly FOXO4-specific (n = 18), FOXO-family/conserved (n = 24), or extrapolated predominantly from FOXO1/FOXO3/DAF-16 (n = 20); 27 contextual publications on redox biology, senescence, disease, and NRF2 were tracked separately. (3) Results: The strongest FOXO4-specific evidence supports three mechanistic axes: cysteine-dependent redox sensing, stress-regulated nuclear trafficking and coactivator engagement through transportin-1 and p300/CBP, and FOXO4–p53-mediated survival of senescent cells. By contrast, direct FOXO4 regulation of commonly cited antioxidant targets, including SOD2, catalase, sestrins, and GADD45, remains insufficiently demonstrated and is inferred mainly from FOXO3 or broader FOXO-family studies. FOXO4-DRI has shown senolytic activity in preclinical models, including vascular endothelium, but has not been clinically validated. (4) Conclusions: FOXO4 is a redox-responsive transcriptional regulator with well-supported roles in cysteine-based signaling and senescent-cell survival, whereas its target-gene-level antioxidant program remains incompletely resolved. Clinical translation of FOXO4–p53 disruption requires isoform- and tissue-specific validation, pharmacokinetic and delivery studies, long-term toxicology, and explicit assessment of p53-dependent tumor surveillance. Full article

Skin functionalities are instrumental in four main domains: protection, regulation, sensation, and support. However, excessive exposure to ultraviolet (UV) radiation can compromise skin integrity and, in turn, affect its functions, by generating reactive oxygen species (ROS). Aiming to protect skin from UV radiation, sunscreens incorporate UV filters and antioxidants that absorb/reflect UV rays and neutralise free radicals, respectively. Nevertheless, undesired side and ecological effects of conventional UV filters have spurred the search for safer alternatives. Among synthetic antioxidants, thioethers have attracted attention for their redox power and potential medicinal properties. In this context, a library of aminopyrimidine–arylthioether conjugates was synthesised and evaluated for their antioxidant, enzyme-inhibitory and antibacterial activities, as well as for their cytotoxicity in HaCaT cells and potential photoprotective properties. Among the aminopyrimidine-thioethers studied, compound C5 stood out for its antioxidant potential, exhibiting a value of 566.39 mM FeSO₄ equivalents per mM of the compound, while compound C2 showed the highest anti-enzymatic potential, inhibiting elastase (45.58%) and tyrosinase activities (34.66%). Regarding photoprotective activity, compound C13 reduced by 33.74% the ROS production induced by UV radiation exposure, at 100 μM, a non-cytotoxic concentration. Finally, compound C7 inhibited the growth of Staphylococcus epidermidis, Staphylococcus hominis and Cutibacterium acnes, at 30 μM. These preliminary results demonstrate that aminopyrimidine–arylthioethers constitute a new class of compounds warranting further investigation for skin protection. Compound C5 showed antioxidant activity in the FRAP assay, comparable to that of the positive control, BHT. Full article

Three-dimensional (3D) bioprinting has reached a complexity limit where empirical, parameter-by-parameter optimization no longer scales. The dominant mode of artificial intelligence (AI) integration remains AI-augmented, where AI is treated as an analytical addition to a conventional pipeline. We argue that the field is approaching a discontinuous transition towards AI-native bioprinting, in which AI represents the operational layer of system intelligence, not an ancillary tool. A systematic analysis of 365 publications on the intersection of bioprinting and AI (2015–2026), performed through 18 queries organized by the four search axes of the PubMed database, shows that the intersection grew 136 times during the decade, with an acceleration of 3.16 times only between 2024 and 2025. Mapping the publications to the six functional domains reveals a marked asymmetry: clinical translation counts 154 papers, while cell viability prediction—the biological foundation that every closed-loop system requires—counts only three. We define AI-native bioprinting as a system architecture that combines continuous learning, multi-modal sensing fused through visual, mechanical and biological signals, and biologically closed control loops. We present a conceptual shift from printing accuracy to biological intelligence as a success criterion. The transition requires open datasets, consensus biological metrics, inter-laboratory validation, and early regulatory engagement. Full article

Lichen sclerosus (LS) is a chronic inflammatory skin disorder with an incompletely understood molecular pathogenesis. This systematic review aimed to synthesize current evidence on key molecular mechanisms underlying the disease, with a particular focus on immune dysregulation, epigenetic modifications, and tissue remodeling. A structured literature search identified studies employing transcriptomic, epigenetic, and experimental approaches. The strongest evidence consistently supports a central role of immune activation, particularly T cell-mediated responses involving Th1- and Th17-related pathways, accompanied by increased expression of pro-inflammatory cytokines and activation of the NF-κB signaling pathway. Epigenetic and post-transcriptional mechanisms, including dysregulated microRNAs (notably miR-155-5p) and altered DNA methylation patterns, may sustain immune imbalance and fibroblast activation partly via modulation of the FOXO signaling pathway. In parallel, experimental and multi-omics studies highlight enhanced fibroblast activity and extracellular matrix remodeling, largely associated with the TGF-β signaling pathway, linking inflammation with progressive fibrosis. Emerging data also suggest interactions between immune signaling and metabolic alterations, although these findings remain preliminary. Overall, the available evidence indicates that LS may involve a complex interplay between immune, epigenetic, and fibrotic mechanisms. While several molecular pathways and candidate biomarkers have been identified, their clinical relevance requires further validation in larger, well-designed studies. Full article

Background/Objectives: To summarize evidence on whether anodization of titanium implant abutments modifies abutment surface/physical properties, peri-implant soft tissue esthetics, and biological outcomes compared with machined titanium and alternative abutment materials. Methods: This focused narrative review used a structured, reproducible literature search with dual-reviewer screening and data extraction. The study selection pathway was summarized using a PRISMA-style flow diagram for transparency. Searches of PubMed/MEDLINE, EMBASE, CENTRAL, and Google Scholar were performed, supplemented by gray literature screening and manual searching. Laboratory, animal, and human clinical studies evaluating anodized titanium abutments were eligible. Data were synthesized qualitatively across prespecified domains (surface or physical properties, esthetic outcomes, and biological outcomes). Because the work was designed as a narrative review, protocol registration and formal risk of bias appraisal were not undertaken. Results: Thirty-five studies were included (twenty-five in vitro, three animal, and seven human clinical). Anodization modified oxide layer characteristics and surface chemistry, and was commonly associated with increased hydrophilicity. Esthetically, pink or yellow anodized titanium generally reduced discoloration compared with uncolored titanium, particularly when soft tissue and restorative material thickness were sufficient, whereas zirconia most consistently produced the most favorable color outcomes. In vitro studies frequently reported improved early soft tissue cell responses and, in selected protocols, reduced bacterial adhesion. Reported clinical differences in inflammation indices and peri-implant marginal bone changes were small or inconsistent. Conclusions: Anodization can improve the optical masking of titanium and alter surface wettability and chemistry, but evidence for sustained clinical biological benefit remains limited. Current evidence supports anodization primarily as an esthetic adjunct, while long-term peri-implant biological outcomes appear to be driven by multiple clinical factors beyond surface modification. Full article

The escalating global concern regarding bacterial antibiotic resistance in animal production has intensified the search for sustainable and effective alternatives to conventional antimicrobials. In this study, two L. reuteri strains (LBM-Ti195 and LBM-Ti173) are isolated from broiler cecal microbiota that were characterized through an integrated approach, combining phenotypic assays with comparative genomic analysis. Both strains exhibited antibacterial activity against relevant veterinary and foodborne pathogens, including Listeria monocytogenes CECT 934, Staphylococcus aureus CECT 239, Clostridium perfringens Type A, and Campylobacter jejuni CCAMP 162. The inhibitory activity anti-S. aureus increased by more than 10% modifying cultivation conditions, while comparative genomic analysis identified an M23-family metallopeptidase as a potential candidate for pathogen inhibition. Phenotypically, both strains produced folate and metabolized fructooligosaccharides (FOS) and inulin, supporting their potential compatibility with synbiotic formulations. Genome reconstruction reinforces these functional findings by revealing a complete predicted de novo folate biosynthesis pathway. In addition, CAZyme annotation identified higher copy numbers of glycosyltransferases GT2 and GT4 compared with the reference strains, suggesting differences in cell-surface carbohydrate metabolism and exopolysaccharide (EPS)-associated traits. Safety profiling revealed no hemolytic activity or conserved virulence factors under the tested conditions. However, phenotypic tetracycline resistance was detected, and in silico analysis identified an acquired tetW gene in a putative plasmid-associated context, highlighting the importance of an in-depth evaluation of strains with probiotic potential. Collectively, these findings position LBM-Ti195 and LBM-Ti173 as promising avian-derived L. reuteri candidates for next-generation zootechnical probiotic development, while highlighting antimicrobial resistance (AMR) mitigation and further functional validation as essential steps toward safe application. Full article

Background: The sphenoid sinus occupies a strategically central position at the base of the skull, in close proximity to critical neurovascular structures including the pituitary gland, optic nerves, internal carotid arteries, and the cavernous sinus. Its complex anatomical configuration and pronounced individual variability render it a structure of paramount clinical importance in transsphenoidal approaches to the sellar and parasellar regions. Methods: A narrative review of the literature was conducted in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) guidelines for narrative reviews. A comprehensive search was performed across four electronic databases—PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar—covering publications from January 2000 through March 2026, with the final search update completed in March 2026. An initial pool of 826 articles was identified. Following title and abstract screening, 421 articles were retained for full-text assessment; of these, 307 contributed to the conceptual synthesis, and 100 are directly cited in the manuscript. The literature selection process followed a structured flow diagram consistent with PRISMA reporting principles for identification and screening stages. Results: We synthesise current evidence on the embryological development, macroscopic and microscopic anatomy, morphological classifications, and epidemiological distribution of anatomical variations in the sphenoid sinus, with emphasis on radiological assessment and surgical relevance. The spectrum of pneumatization patterns—from the conchal type through presellar and sellar variants to the postsellar, clival, and lateral types—is reviewed alongside population-level prevalence data. Common and rare variations are examined, including intrasinus septation, Onodi cells, and bony dehiscences overlying the internal carotid artery and optic nerve. The comparative diagnostic capabilities of computed tomography and magnetic resonance imaging are evaluated, alongside emerging modalities such as three-dimensional reconstruction, virtual reality, and augmented reality. Conclusions: Detailed morphological knowledge of the sphenoid sinus plays an important role in surgical strategy, instrument selection, and risk mitigation in skull base surgery. Individualised preoperative imaging—integrating CT, MRI, and, where available, immersive digital technologies—is essential for safe transsphenoidal planning and cannot be replaced by standard anatomical templates. Full article

Background: Intra-articular (IA) stem cell injection is an emerging treatment for knee osteoarthritis (KOA). Three principal cell sources—adipose-derived mesenchymal stem cells (ADMSCs), bone marrow-derived MSCs (BMMSCs), and peripheral blood-derived stem cells (PBSCs)—have been evaluated independently; however, a systematic review comprehensively comparing all three sources under unified eligibility criteria is absent from the literature. Methods: Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, and Scopus were conducted from inception to December 2025, supplemented by manual reference screening and ClinicalTrials.gov. Eligible studies included randomized controlled trials (RCTs) and prospective comparative studies in adult KOA patients. Primary outcomes were pain (VAS/NRS) and function (WOMAC, KOOS) at ≥3 months. Risk of bias was assessed using RoB 2 and ROBINS-I; evidence certainty was rated using GRADE. Results: Thirty-one studies (n = 1247; ADMSC: 14 studies, n = 612; BMMSC: 12 studies, n = 487; PBSC: 5 studies, n = 148) met inclusion criteria. Pooled standardized mean differences (SMDs) for 6-month pain showed significant reduction versus comparators for ADMSCs (SMD −1.23; 95% CI −1.61 to −0.85; I² = 62%) and BMMSCs (SMD −1.09; 95% CI −1.55 to −0.63; I² = 70%). PBSCs demonstrated significant within-group improvement but were too few for formal pooling. Because no trial compared cell sources head-to-head, these estimates reflect within-source efficacy versus each study’s own comparator rather than comparative superiority between sources. Adverse events were mild and transient across all sources. GRADE certainty was moderate for ADMSCs, low for BMMSCs, and very low for PBSCs. Conclusions: IA injection of ADMSCs and BMMSCs provides pain reduction and functional improvement in KOA with point estimates reaching minimal clinically important difference thresholds, although the certainty of this evidence is only moderate (ADMSC) to low (BMMSC). PBSC evidence is insufficient for formal comparison. Adequately powered, three-arm head-to-head RCTs that share a common comparator and a core outcome set are needed to establish comparative efficacy. Because only indirect comparisons were possible, this review supports efficacy within each cell source but cannot establish the superiority of one source over another. Full article

Type 1 diabetes (T1D) is an autoimmune disease characterized by β-cell destruction as a common trait, in which variability in age at onset, progression rate, and clinical presentation shape heterogeneous phenotypes. Disentangling this heterogeneity is pivotal for a better understanding of clinical risk, evolution and a precision medicine approach to the disease. In this context, circulating islet autoantibodies, including the last discovered Zinc Transporter 8 autoantibodies (ZnT8A), represent crucial tools. This narrative review provides an overview of the current knowledge on ZnT8A in autoimmune diabetes from its structural and pathogenetic basis to its clinical relevance and therapeutic perspectives. A literature search was conducted in PubMed, Scopus, Google Scholar, and ResearchGate up to March 2026, that included preclinical, pediatric, adult, and assay-comparison studies. While the identification of ZnT8-targeted antigenic determinants is still ongoing, we discuss the pathogenic role of a newly identified specific class of antibodies directed against extracellular ZnT8 epitopes (ZnT8ecA). According to this finding, ZnT8ecA could facilitate the identification of an early phase of islet injury process, holding promise to provide a framework for new therapeutic strategies based on masking or modulating surface-exposed ZnT8 epitopes and interfering with the early stages of the disease. Moving from the role of ZnT8A in various clinical settings, we also focus on recent advancements in detection technologies, whose implementation accounts for invaluable contributions to diagnosis, disease risk, and, contextually, to a better understanding of autoimmune diabetes. Finally, we provide future perspectives, in T1D and T1-related diseases, for the potential clinical application of ZnT8A in early diagnosis, risk stratification and profiling, as well as in the development of targeted therapies as part of precision medicine. Full article

Type 2 diabetes (T2D), a major global health challenge, represents approximately 96% of all cases of diabetes worldwide. Epidemiological forecasts indicate the prevalence of this disease could rise by almost 45% over the next 25 years. T2D is a chronic metabolic disorder characterised by insulin resistance and progressive impairment of β-cell function. Untreated T2D can lead to serious microvascular and macrovascular complications. Traditional therapies have focused primarily on glycaemic control, whereas modern treatment strategies are increasingly centred on the broader pathophysiology of T2D. Among new therapeutic approaches, triazine derivatives have gained significant attention as versatile scaffolds for the development of antidiabetic drugs. This article provides a comprehensive review of triazines (mainly 1,2,4-triazines and 1,3,5-triazines) as promising compounds for the treatment of T2D and its complications. Three databases (Scopus, PubMed, and Web of Science) were searched for the period of 2000–2025. Over the past 25 years, numerous compounds have been described. They were primarily investigated as inhibitors of digestive enzymes and factors that cause diabetic complications. The individual sections discuss the biological activity of these compounds, focusing on SAR analysis and the studies conducted (in vitro, in silico, and in vivo). During this period, two compounds, fotagliptin and imeglimin, have entered clinical use. The results show that triazines have great potential to become antidiabetic drugs. They can not only regulate blood sugar levels (by acting on digestive enzymes, insulin secretion or glucose transport) but also directly prevent serious complications of diabetes. Full article

Background/Objectives: Outcomes after CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) aggressive large B-cell lymphoma (aLBCL) remain heterogeneous. Tumor genomic biomarkers, such as TP53 alteration, MYC/BCL2/BCL6 rearrangement-defined double-hit or triple-hit lymphoma (DHL/THL), cell of origin (COO), and complex karyotype, are established or candidate prognostic factors in conventionally treated lymphoma, but their relevance after CAR T-cell therapy is uncertain. We conducted a systematic review with exploratory meta-analysis of biomarker-stratified outcomes after CD19 CAR T-cell therapy in aLBCL. Methods: We searched MEDLINE, Embase, and Web of Science/BIOSIS (April 2026), with targeted PubMed citation lookup during full-text retrieval (PROSPERO CRD420261350514). Eligible studies enrolled adults with R/R disease treated with protocol-eligible CD19 CAR T-cell therapy and reported prespecified tumor genomic biomarkers with stratified outcomes. Random-effects models, using restricted maximum-likelihood estimation with Hartung–Knapp–Sidik–Jonkman (HKSJ) adjustment, were fitted when at least three comparable, non-overlapping studies provided extractable data. Results: After duplicate removal, 182 records were screened, 37 were assessed for eligibility, and 26 studies were included in the qualitative synthesis; 10 contributed to 4 pooled analyses. DHL/THL-positive disease was associated with worse unadjusted overall survival (OS) (hazard ratio [HR] 1.52; 95% confidence interval [CI], 1.21–1.89; 95% prediction interval (PI), 0.56–4.08), and non-Germinal center B-cell-like (GCB)/ABC COO with worse adjusted progression-free survival (PFS) (HR 1.44; 95% CI, 1.04–2.00; 95% PI, 0.86–2.43). The complete-response analyses for TP53 alteration (OR 1.30; 95% CI, 0.01–156.60) and COO (OR 1.27; 95% CI, 0.24–6.61) were statistically uninformative. No study permitted evaluation of complex karyotypes. Conclusions: Biomarker-stratified evidence after CD19 CAR T-cell therapy is sparse and inconsistently reported. DHL/THL status and non-GCB/activated B-cell-like (ABC) COO showed exploratory survival signals, whereas the TP53 and COO complete-response analyses were uninformative. These biomarkers remain hypothesis-generating rather than validated predictors of CAR T-cell outcome, and standardized, prospective biomarker-stratified reporting is needed. Full article

MET pathway alterations have evolved from a niche translational interest into one of the most clinically actionable axes in non-small cell lung cancer (NSCLC). Three biologically distinct lesions—MET exon 14 (METex14) skipping mutations, focal high-level MET amplification, and c-Met protein overexpression—are now individually targetable, each with its own diagnostic prerequisites and therapeutic class. Selective type Ib MET tyrosine kinase inhibitors (capmatinib, tepotinib) anchor first-line therapy for METex14, while next-generation agents and type II inhibitors are being developed to address on-target D1228 and Y1230 resistance mutations. In parallel, MET amplification has emerged as a leading mechanism of acquired resistance to osimertinib in EGFR-mutated NSCLC, with the SAVANNAH, SACHI, and INSIGHT 2 trials providing biomarker-guided combination strategies. The 2025 accelerated approval of telisotuzumab vedotin for c-Met-overexpressing tumors expanded the therapeutic armamentarium beyond kinase inhibition. Despite these advances, lineage plasticity, polyclonal bypass signaling, and inconsistent diagnostic thresholds for MET amplification continue to limit durable benefit. This review integrates the molecular biology, current clinical evidence, resistance mechanisms, and a proposed 2025 treatment algorithm for MET-altered NSCLC, with emphasis on the translational interface between mutation class, drug class, and emerging combinatorial approaches. As a narrative review, it synthesizes peer-reviewed literature and pivotal trial and regulatory data through early 2026, identified by structured searches of PubMed and major oncology congress proceedings, and prioritizes sources that link mutation class to drug class and resistance mechanism. Full article