Search Results (2,607)

Glioblastoma (GB) remains one of the most therapy-resistant solid tumors, characterized by profound metabolic plasticity, intratumoral heterogeneity, and a highly immunosuppressive microenvironment. While immunotherapies such as chimeric antigen receptor T (CAR-T) cells have shown promise in hematological malignancies, their efficacy in GB has been limited. Emerging evidence suggests that tumor-specific metabolic dependencies and post-translational modifications (PTMs) may represent exploitable vulnerabilities. This review discusses disulfidptosis, a recently described form of regulated cell death driven by disulfide stress under conditions of limited reducing capacity, as a context-dependent metabolic–redox vulnerability in GB. We further discuss how altered protein glycosylation and glycocalyx architecture in glioblastoma regulate cell survival, death signaling, and immune recognition. Particular emphasis is placed on the glycosylation of surface antigens targeted by CAR-T cells, including EGFR/EGFRvIII, IL-13Rα2, mesothelin, B7-H3, HER2, and GD2, and on how glycan-dependent epitope accessibility may limit therapeutic efficacy. Finally, we distinguish disulfidptosis, whose direct relevance to CAR-T-cell responses remains to be established, from glycosylation and glycocalyx remodeling as more direct determinants of target–antigen accessibility and immune recognition. Therapeutic strategies addressing these vulnerabilities may provide rational opportunities to improve CAR-T-based and combinatorial therapies for GB. Full article

Angiostrongyliasis, the primary cause of eosinophilic meningitis, represents an emerging disease caused by Angiostrongylus cantonensis larvae, inadvertently transmitted to humans. The diagnosis of human angiostrongyliasis relies on epidemiological features, clinical symptoms, medical history, and laboratory findings, notably hyper eosinophilia in blood and cerebrospinal fluid. Consequently, accurate diagnosis is challenging and prone to confusion with other parasitic diseases. The quest for an early, rapid, and specific diagnostic test for angiostrongyliasis persists, driven by the imperative for enhanced test specificity. This study focused on mapping IgM epitopes on galectin-1 (Gal-1) and galectin-2 (Gal-2) proteins derived from A. cantonensis. The specificity of the epitopes was assessed using database homology analysis. After selecting specific epitopes, researchers chemically synthesized 12 individual multi-antigen peptides (MAPs4) and one chimeric polypeptide that is 65 amino acids long. The effectiveness of these synthesized peptides was subsequently evaluated using enzyme-linked immunoassay (ELISA). A total of twelve unique IgM epitopes were discovered; five were linked to Gal-1, while seven were linked to Gal-2. An ELISA-peptide method confirmed the twelve epitopes, and then the chimeric polypeptide was employed as an antigen to coat ELISA plates. This setup was evaluated with patients’ sera to diagnose strongyloidiasis in vitro. This study provides a comprehensive representation of the IgM epitopes of Gal-1 and Gal-2 from A. cantonensis. ELISA data utilizing the chimeric polypeptide demonstrate that the selected sequences hold promise for the development of a specific immunological assay tailored for the acute diagnosis of angiostrongyliasis infections. Full article

Background: Chagas disease, caused by Trypanosoma cruzi, remains a major public health problem in Latin America and an emerging concern worldwide. Current chemotherapies show limited efficacy during chronic infection, and no licensed vaccine is currently available. We previously developed the chimeric antigen N-Tc52/TSKb20 as a vaccine candidate against T. cruzi infection. In a murine model, this vaccine induced robust antigen-specific immune response associated with protection shortly after vaccination. Objectives: Here, we investigated the long-term persistence and effector functions of the immune responses elicited by this vaccine candidate. Methods: Both female and male C57BL/6 mice were immunized with three doses of N-Tc52/TSKb20 formulated with QuilA adjuvant. Serum samples collected 170 days post-immunization were analyzed for antigen-specific antibodies by ELISA and for trypanolytic activity against cell-derived trypomastigotes using an in vitro functional assay. Cellular immune responses were evaluated by measuring cytokine production, T cell activation, and memory T cell responses following in vitro re-stimulation with the vaccine antigen or T. cruzi antigens. Results: N-Tc52/TSKb20 vaccination induced a sustained antigen-specific humoral response, characterized by long-lasting IgG2c antibodies and functional activity persisting for up to 170 days post-immunization. In parallel, vaccination promoted long-term activation of antigen-specific CD8⁺ T cells and production of TNF-α and IFN-γ upon antigen re-encounter. A sex-dependent tendency was observed for IL-10, with increased production in vaccinated female mice. Moreover, vaccinated animals exhibited increased frequencies of central and effector memory CD4⁺ and CD8⁺ T cells in response to T. cruzi antigens, with a predominant contribution of CD8⁺ T cells, indicating the establishment of parasite-specific T cell memory. Conclusions: Together, these findings demonstrate that vaccination with N-Tc52/TSKb20 induces a long-lasting Th1-biased immune response characterized by trypanolytic antibodies, functional and durable T cell responses, and parasite-specific memory T cells. This immunological profile supports the potential of N-Tc52/TSKb20 as a promising vaccine candidate for Chagas disease and highlights its capacity to elicit immune mechanisms that have been associated with protection against T. cruzi infection. Full article

Brucellosis is a globally prevalent zoonotic disease affecting both humans and animals. Its nonspecific clinical manifestations often complicate diagnosis, underscoring the need for reliable laboratory confirmation. Traditional serological assays, though widely used, suffer from limitations such as inconsistent sensitivity and false-positive results. To address these challenges, this study mapped IgM and IgG epitopes of the Brucella Omp-2a protein using sera from infected patients. Epitope identification was performed through SPOT synthesis on cellulose membranes, followed by assessment of potential cross-reactivity using peptide database analysis and ELISA validation. Three major IgM and seven IgG linear B-cell epitopes were identified, six of which demonstrated strong reactivity in peptide-ELISA. Importantly, no significant cross-reactivity with proteins from other human pathogens was detected. Two chimeric multi-epitope peptides, composed of 50 and 60 amino acids and integrating Brucella-specific IgM and IgG epitopes, exhibited excellent diagnostic performance in ELISA, achieving near 100% sensitivity and specificity. These findings support the potential of synthetic peptides as reliable and cost-effective alternatives to native antigens in serological assays. Further validation in larger, geographically diverse cohorts will be essential to confirm their diagnostic robustness and facilitate their integration into routine brucellosis diagnostics. Full article

Triple-negative breast cancer (TNBC), characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is a highly aggressive molecular subtype with high recurrence and metastasis rates. Due to the absence of reliable molecular targets, surgery combined with chemotherapy remains the mainstay of clinical treatment. In recent years, immunotherapy has provided new strategies for TNBC management. Immune checkpoints are key regulatory molecules that maintain immune homeostasis, and blocking these checkpoints can restore T cell activity and enhance tumor cell killing. Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit, particularly in combination with chemotherapy for patients with locally advanced or metastatic TNBC. This review focuses on immune checkpoint–based immunotherapy in TNBC, providing an overview from mechanistic insights to clinical applications and emerging therapeutic strategies. In addition to ICIs, we discuss alternative approaches, such as bispecific antibodies, antibody–drug conjugates (ADCs), chimeric antigen receptor T cell (CAR-T) therapy, tumor vaccines, and oncolytic viruses (OVs), highlighting their current research progress and clinical applications in TNBC treatment. Full article

Macrophages are highly plastic innate immune cells that adopt context-dependent phenotypes along a continuum, integrating developmental origin with local microenvironmental cues rather than conforming to discrete M1/M2 states. This review delineates the molecular circuits shaping macrophage identity—TLR/cytokine signaling, microRNA networks, metabolic rewiring, and epigenetic mechanisms including histone lactylation—and traces how circulating monocyte subsets contribute to tissue macrophage diversity. We examine macrophage plasticity across a broad disease spectrum—oncology, autoimmune and rheumatic diseases, inflammatory bowel disease, infectious diseases, metabolic disorders, and neurological conditions—showing that the pathogenic phenotype is strikingly context-dependent: for instance, M2-like tumor-associated macrophages promote immune evasion in solid tumors, whereas M1-skewed programs drive tissue damage in autoimmunity. Soluble markers (sCD163, sCD14, soluble mannose receptor) are emerging biomarkers of disease activity and prognosis. High-dimensional flow cytometry and mass cytometry (CyTOF) bridge molecular biology and clinical phenotyping, enabling integrated readouts of surface phenotype, intracellular signaling, and metabolic state. Therapeutic strategies discussed include selective tumor-associated macrophage (TAM) reprogramming, chimeric antigen receptor (CAR)-M cell therapies, and biomaterial-based platforms. Future priorities encompass spatially resolved multi-omics, epigenetic and metabolic targeting, and macrophage-centered vaccine approaches. Standardized cytometry panels will be essential for biomarker-guided stratification and context-specific interventions. Full article

The development of pathogen-associated molecular patterns (PAMPs) that signal via pathogen recognition receptors (PRRs) on innate immune cells is a strategy that is widely adopted in adjuvant research. Less well studied is how covalently linking different PAMPs affects the immune response. Herein, we summarise the research on the effect of PAMP linkage on innate and adaptive immune responses. These covalently linked or “chimeric” PAMPs often lead to immune cell synergies that are greater than those exhibited by the admixed (unconjugated) PAMPs, with several PAMP conjugates exhibiting remarkable adjuvant activity in a variety of disease contexts that include infectious disease, allergy, and cancer immunotherapy. This improvement in immune cell activation is thought to be due to more effective crosstalk between the different PRR signalling pathways, as conjugation ensures that each cell receives each class of PAMP. In addition, PAMP conjugates can form particulates, which has been postulated to lead to improved adjuvanticity, or they may facilitate the targeting of endosomal PRRs via the PRR-mediated endocytosis of the alternative PAMP in the conjugate. PAMP conjugates can also reduce the toxicity of individual PAMPs. However, not all PAMP conjugates are effective, and there are still many aspects of this research platform that are poorly understood, including how linker chemistry affects the immune response and how PRR signalling pathways or PAMP combinations combine to skew the immune response. We will address these and other outstanding questions that relate to the use of PAMP conjugates as vaccine adjuvants. Full article

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the management of relapsed or refractory hematologic malignancies, achieving high response rates in B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and multiple myeloma. While the efficacy of CAR-T therapy is well established, quality of life (QoL) metrics have become increasingly important for guiding treatment decisions, patient counseling, and survivorship planning. Objectives: Most patients undergoing CAR-T therapy recover their initial QoL within 3 months, an improvement not typically seen with other treatment options. A comprehensive understanding of QoL is essential for delivering patient-centered care in the evolving CAR-T landscape. Conclusions: This review synthesizes current evidence on QoL outcomes in CAR-T recipients, including acute effects, recovery trajectories, comparisons with conventional therapies, and strategies to optimize QoL. Full article

The myocardium possesses one of the highest vascular densities in the body. The outermost wall layer of large and medium-sized vessels, the adventitia, forms a critical interface between the vasculature and the myocardium and serves as a reservoir for stem and progenitor cells capable of differentiating into all vascular wall lineages as well as innate immune cells, including macrophages. Current cardiac organoid models intrinsically develop networks of endothelial cords and small capillary-like structures that resemble cardiac microvessels. However, these microvessels mostly lack an adventitial compartment in vivo. Here, we present a potential alternative assembloid strategy that combines vascular segments from mouse and human origin with either cardiomyocytes or cardiac spheroids derived from human induced pluripotent stem cells, thereby incorporating large diameter vessels and the vascular adventitia into a cardiac tissue model. Within the assembloids, the myocardial component remained contractile and connected to the vascular adventitia, which displayed cellular sprouting toward the hiPSC-derived cardiac tissue. Immunostaining for vascular and immune markers revealed that the adventitia gave rise to endothelial sprouts and macrophage-like cells which integrated into the myocardial tissue. In summary, we present proof of concept for complex assembloids composed of vessel segments and human iPSC-derived cardiomyocytes which contain and maintain an in vivo-like adventitial compartment. We suggest this model may serve as a platform for investigating myocardial–stromal interactions, cardiac tissue repair, and functional remodeling under both physiological and pathological conditions. Furthermore, the incorporation of large-lumen vessel segments may enable future experimental perfusion, rendering the model particularly suitable for drug testing via intravascular delivery. Full article

Simultaneous autologous breast reconstruction (ABR) and lymphatic surgery has emerged as a strategy to address breast cancer-related lymphedema (BCRL) while restoring breast contour within a single operative procedure. In light of the diversity of surgical strategies, we aimed to evaluate the current literature on combined ABR and lymphatic surgery, with particular focus on surgical techniques, clinical outcomes, complications, and patient-reported satisfaction. A systematic review was conducted according to PRISMA guidelines and registered in PROSPERO (CRD420251135446). Medline, Embase, CENTRAL, Web of Science, and PubMed were searched through 9 January 2026 Studies reporting outcomes of simultaneous ABR and lymphatic reconstruction were included. Data on surgical techniques, complications, changes in limb volume and cellulitis incidence, and patient-reported outcomes were extracted. Twenty-seven studies including 499 patients (mean follow-up 23 months) were analyzed. The most common approach was a chimeric deep inferior epigastric perforator (DIEP) flap with inguinal lymph nodes (459 patients), followed by ABR with a separate vascularized lymph node transfer and ABR with lymphovenous anastomosis. Most studies reported postoperative reductions in limb volume and cellulitis, with cellulitis reduction rates up to 100%. Patient-reported outcomes (LYMQOL, ULL-27, LYMPH-Q) showed improved quality of life. Complication rates were low, including 4% seroma and 1% flap loss after chimeric DIEP. Simultaneous ABR and lymphatic reconstruction is feasible and associated with improved clinical and patient-reported outcomes. However, heterogeneity limits comparison between the different surgical techniques, and prospective studies with standardized outcomes measurements are needed. Full article

Relapse remains the leading cause of treatment failure following hematopoietic cell transplantation (HCT) for hematologic malignancies. Circulating tumor DNA (ctDNA) has emerged as a promising minimally invasive biomarker for measurable residual disease (MRD) assessment and early relapse detection; however, the prognostic significance of ctDNA in the post-transplant setting has not been comprehensively synthesized. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines and registered the protocol in PROSPERO (CRD420261392100). PubMed, Embase, Web of Science, EBSCO, Cochrane CENTRAL, and supplementary sources were searched through November 2025. Eligible studies evaluated tumor-specific ctDNA or tumor-informed/tumor-associated cfDNA in patients undergoing allogeneic or autologous HCT for hematologic malignancies. Random-effects meta-analyses were performed for relapse/progression, overall survival (OS), and relapse-free/progression-free survival (RFS/PFS). Studies evaluating total cfDNA quantity, methylation-based cfDNA profiling, cfRNA, or chimerism-only monitoring were synthesized narratively. Ten observational cohort studies comprising 883 patients met inclusion criteria. Across acute leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes, ctDNA/cfDNA positivity was consistently associated with adverse outcomes. The pooled hazard ratio (HR) for relapse or disease progression was 12.57 (95% CI: 4.59–34.46; p < 0.001), while pooled HRs were 7.45 (95% CI: 4.11–13.48; p < 0.001) for OS and 4.46 (95% CI: 2.22–8.97; p < 0.001) for RFS/PFS. Although statistical heterogeneity was low, interpretation was limited by the relatively small number of studies contributing to each pooled endpoint. Narrative evidence additionally suggested that broader circulating nucleic acid approaches may provide complementary information regarding graft-versus-host disease, infection, and other post-transplant complications. Tumor-specific ctDNA positivity is consistently associated with increased relapse risk and inferior survival outcomes following HCT. These findings support further investigation of ctDNA-based MRD monitoring as a promising non-invasive biomarker for post-transplant molecular surveillance and risk stratification. However, prospective multicenter validation studies, assay standardization, and ctDNA-guided interventional trials remain necessary before routine clinical implementation can be recommended. Full article

Chimeric antigen receptor T (CAR-T) cell therapy has transformed the treatment of hematologic malignancies, yet its broader application, particularly in solid tumors, remains constrained by high cost, labor-intensive manufacturing, limited production capacity, and variable clinical performance, as well as barriers such as poor trafficking, antigen heterogeneity, and an immunosuppressive tumor microenvironment. In vivo CAR-T cell engineering, in which CAR-T cells are generated directly within the patient, offers a paradigm shift by eliminating the need for ex vivo cell processing and complex logistical infrastructure. Among emerging approaches, messenger RNA (mRNA)-loaded lipid nanoparticles (LNPs) have emerged as a promising and clinically tractable platform for in vivo CAR-T cell generation, enabling direct reprogramming of T lymphocytes within the patient and thereby circumventing the need for leukapheresis, viral vector production, and prolonged ex vivo culture, effectively transforming the patient into their own cell therapy factory. This review synthesizes advances in mRNA-LNP-mediated in vivo CAR-T cell generation, encompassing ionizable lipid chemistry and emerging T cell-targeted delivery strategies, including surface functionalization approaches. We discuss the implications of transient CAR expression for immune activation, safety, and therapeutic durability, alongside CAR design optimization through co-stimulatory domains and safety switches. Preclinical evidence from murine tumor models and non-human primates is integrated with current regulatory considerations, and key barriers to clinical translation are highlighted. Collectively, progress in nucleic acid delivery, synthetic immunology, and precision medicine positions in vivo mRNA-CAR-T therapy as a promising modality for oncology and beyond. Full article

Prophages are bacteriophage genomes that are part of bacterial chromosomes. They are not just dormant passengers; they actively shape pathogen biology. For example, in skin-infecting pathogens such as Staphylococcus aureus, Streptococcus pyogenes, and Pseudomonas aeruginosa, prophages carry important virulence factors, cytotoxins, superantigens, immune evasion clusters, and epigenetic regulators that directly affect the course of skin and soft tissue infections. This same prophage biology provides a therapeutic strategy: prophage-derived molecules, including endolysins, holins, spanins, and polysaccharide depolymerases, demonstrate potent antimicrobial and antibiofilm activity against drug-resistant skin pathogens, with several candidates now in clinical development. Engineered chimeric lysins, CRISPR-encoded prophage delivery systems, and the systematic mining of the skin microbiome phageome collectively enhance the translational potential of this biology. This review integrates mechanistic insights into prophage-mediated virulence. It assesses the translational landscape of prophage-derived therapeutics, delineating the conceptual and clinical frontiers that characterize the forthcoming chapter in this domain. Full article

Hematological malignancies encompass a broad spectrum of relatively rare cancers with diverse biological and clinical characteristics that are capable of affecting individuals across all age groups, though certain subtypes show a predilection for specific age ranges. Advances in next-generation sequencing have greatly enhanced our understanding of the molecular and genetic basis of these diseases, while epigenetic, transcriptional, and proteomic analyses have further clarified their pathogenesis. These developments have shaped the classification and treatment of lymphoma. Updated classification frameworks which include the identification of clinically relevant molecular targets have opened the door to a number of targeted agents, each designed to exploit specific vulnerabilities within malignant cells, while stem cell transplantation continues to offer curative potential for eligible patients, with improving safety profiles over time. CAR-T-cell therapy has been extended to multiple blood cancer indications, achieving lasting remissions in patients with previously exhausted treatment options. Bispecific antibodies have further broadened the immunotherapy landscape by redirecting the body’s own T cells against tumor cells, offering a readily available alternative that overcomes many of the practical limitations associated with CAR-T-cell production. The ability to combine these strategies has fundamentally changed what is achievable in blood cancer treatment, with long-term remission now a realistic goal for many patients. This review seeks to outline the core molecular mechanisms underlying lymphoma and leukemia, evaluate currently approved treatment options, discuss significant ongoing clinical trials with practice-changing potential, and explore the prospect of chemotherapy-free approaches in carefully selected patient groups. Full article

(1) Background: Cognitive dysfunction represents an emerging concern in chimeric antigen receptor T-cell (CAR-T) therapy recipients, yet longitudinal data using simple, clinically applicable tools are lacking. (2) Methods: We conducted a single-center prospective cohort study of consecutive adults with hematologic malignancies treated with commercially available CAR-T cell products between May 2023 and November 2025 at our center. Cognitive function was evaluated with the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) at baseline (before the administration of lymphodepleting chemotherapy) (T1), 6 h after infusion (T2), at 3 months (T3), and at 6 months (T4). MoCA scores ≤ 25 and/or MMSE scores ≤ 23 were considered indicative of impaired cognitive function. (3) Results: Thirty-six patients were enrolled in the present study, while cytokine release syndrome occurred in 33/36 patients (91.7%), and immune effector cell-associated neurotoxicity syndrome of any grade occurred in 23/36 (63.9%). At baseline (T1), cognitive impairment was identified in 12/36 patients (33.3%) by MoCA. Following infusion (T2), 11/35 (31.4%) exhibited cognitive impairment, while baseline cognitive impairment and older age were associated with early post-infusion cognitive dysfunction. Across follow-up (T3 and T4), no significant overall changes were observed in MoCA- or MMSE-defined cognitive status or in total test scores. However, abstraction in MoCA and attention/calculation in MMSE showed time-dependent variation. (4) Conclusions: These findings support the use of simple longitudinal cognitive assessment in CAR-T recipients. Full article