Search Results (26,206)

Background/Objectives: Teclistamab is a B-cell maturation antigen (BCMA)-directed bispecific antibody approved for relapsed or refractory multiple myeloma (RRMM). Although prior analyses have summarized teclistamab outcomes, some have included combination regimens or broader comparative studies. Given the expanding real-world experience with teclistamab, we conducted a systematic review and meta-analysis focused on teclistamab monotherapy in RRMM. Methods: We performed a systematic review and meta-analysis of clinical trials and retrospective real-world studies evaluating teclistamab monotherapy in RRMM. The primary endpoint was overall response rate (ORR). Secondary endpoints included complete response (CR), overall mortality rate (OMR), mortality due to multiple myeloma progression, teclistamab-attributed mortality, adverse event-related mortality, grade ≥3 cytokine release syndrome (CRS), grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS), and other grade ≥3 adverse events. Pooled proportions were estimated using random-effects models. Results: Twelve studies including 761 patients were analyzed, comprising two clinical trials and ten real-world retrospective cohorts. The pooled ORR was 60.9%, and the pooled CR rate was 25.2%. The pooled OMR was 26.9%, with mortality due to myeloma progression of 23.9%, adverse event-related mortality of 8.1%, and teclistamab-attributed mortality of 3.3%. Severe (grade ≥3) CRS and ICANS were uncommon, with grade ≥3 events occurring in 1.7% and 3.1%, respectively. Grade ≥3 infections occurred in 28.3%. Common grade ≥3 hematologic adverse events included lymphopenia, neutropenia, anemia, and thrombocytopenia. Conclusions: Teclistamab monotherapy demonstrates meaningful clinical activity and a manageable immune toxicity profile in heavily pretreated RRMM. However, severe infections and hematologic toxicities remain important clinical considerations, supporting the need for close monitoring, infection prevention, and supportive care during therapy. Full article

Covalently closed circular DNA (cccDNA) is a stable episomal form of the hepatitis B virus (HBV) genome that serves as the template for viral transcription and replication and represents a major barrier to HBV cure. Here, we investigated chromatin accessibility patterns of cccDNA in HBV-infected hepatocyte cells at single-molecule resolution. We found that most cccDNA copies exhibited limited accessibility around nucleotides 800–1000, a region overlapping the polymerase open reading frame and the pregenomic RNA transcriptional region. Notably, a small subset of cccDNA showed detectable accessibility at this site, suggesting the presence of heterogeneous chromatin states. Based on this observation, we targeted this accessibility-associated region using a CRISPR/Cas9-based approach and observed reductions in HBV DNA-related signals, including cccDNA-enriched fractions and total HBV DNA levels across complementary experimental systems. These findings suggest that chromatin accessibility profiling may provide an additional framework for identifying candidate cccDNA target regions. Our study provides a proof-of-concept for accessibility-informed HBV targeting and supports further investigation of chromatin-associated vulnerability within HBV cccDNA. Full article

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) cause recurrent skin infections that are difficult to treat because of the limited solubility and permeability of acyclovir (ACV). This study developed electrospun polymeric membranes based on polycaprolactone (PCL), poly(lactic acid) (PLA), and cellulose acetate (CA) as controlled ACV delivery systems using uniaxial and coaxial fiber architectures. In the coaxial configuration, ACV-loaded PCL was used as the core and a PLA/CA blend as the shell. Continuous, randomly oriented, bead-free fibers with diameters ranging from 0.68 ± 0.32 µm to 1.45 ± 0.57 µm were obtained. Spectroscopic and thermal analyses confirmed successful drug incorporation, polymer compatibility, and good thermal stability. Coaxial membranes exhibited improved mechanical properties compared with uniaxial systems. Drug release studies showed a prolonged, pH-dependent profile, with greater ACV release at pH 7.3 than at pH 5.5, indicating the effective modulation of drug diffusion by the shell layer. Release kinetics were mainly governed by diffusion and anomalous transport mechanisms. All membranes maintained a cell viability above 80%, demonstrating good in vitro cytocompatibility. These findings support the potential of coaxial electrospun membranes for controlled antiviral drug delivery in skin applications. Full article

Background: DNA Ligase 4 (LIG4) catalyzes the final ligation step during V(D)J recombination. Biallelic pathogenic variants in LIG4 cause severe combined immunodeficiency (SCID), a life-threatening immunodeficiency characterized by the lack of mature T and B cells. Case Presentation: An 18-year-old male exhibited widespread verrucous and keratotic cutaneous lesions across the face, neck, and extremities. The proband manifested early-onset short stature, chronic malnutrition, recurrent pulmonary infections with bronchiectasis, chronic diarrhea, and bilateral tenosynovitis. Immunophenotyping revealed persistent panhypogammaglobulinemia, absent B cells, reduced T and natural killer (NK) cells, and nearly undetectable naïve T cells. Both α-HPV and β-HPV were detected in the cutaneous lesions. Compound heterozygous LIG4 variants (hg19, NM206937.2, c.833G > T; p.Arg278Leu inherited from the mother; c.833G > A; p.Arg278 His inherited from the father) were identified. Conclusions: This study reports a proband with LIG4 syndrome presenting with rare phenotypes of multiple viral warts and combined lymphopenia of T, B, and NK cells. This proband harbors compound heterozygous variants at the same codon (c.833G), which not only confirm the clinical diagnosis but also enrich the known phenotypic spectrum of LIG4 syndrome. Full article

Tuberculosis (TB) and chronic obstructive pulmonary disease (COPD) remain global public health challenges, yet the mechanisms underlying their comorbidity remain poorly understood. COPD is associated with an increased risk of active TB, but the cellular and molecular basis of this association remains unclear. A growing body of evidence suggests that TB is not limited to an intramacrophage infection but is accompanied by a disruption of the local immune balance in lung tissue. This review analyzes the early interface of host–Mycobacterium tuberculosis (Mtb) interaction—from pattern recognition signaling pathways and metabolic reprogramming of macrophages to epithelial barrier responses and the delayed αβ T cell response. This review evaluates γδ T cells, particularly phosphoantigen (pAg)-reactive Vγ9Vδ2 cells, as a candidate early integrative component of the host response, positioned between macrophage infection, epithelial stress, mycobacterial antigens, and bacille Calmette–Guérin (BCG)-induced trained immunity. Available evidence suggests that COPD-associated immune alterations may impair mucociliary clearance, antimicrobial peptide production, phagocytosis, and innate T cell responses while favoring cytotoxic reactions, the IL-17A–G-CSF–neutrophil axis, and protease-mediated tissue damage; however, direct mechanistic evidence in patients with TB–COPD remains limited. It is important to note the differences in data obtained from studies in humans, primates, mice, and in vitro: the Vγ9Vδ2 system has no direct analog in laboratory mice, which represents a key limitation for preclinical studies. A key unresolved question remains the nature and functional consequences of γδ T cell changes in patients with coexisting COPD and TB infection. The answer to this question could inform new strategies for the prevention and treatment of TB in patients with COPD, including BCG revaccination, pAg-mediated immunomodulation, and the development of biomarkers to distinguish between protective and harmful early immune responses. Full article

Newcastle disease virus (NDV) is an important avian pathogen that can circulate in migratory birds, including Larus ridibundus. This study examined the transcriptional responses and anti-NDV activities associated with recombinant IFN-α and Mx proteins from L. ridibundus. The IFN-α and Mx open reading frames were cloned (GenBank: OP263971 and OP263970), expressed using a pET32a(+)/E. coli system, and assessed using chicken embryos, DF-1 cells, and primary gull lymphocytes. qRT-PCR analysis showed that NDV infection increased IFN-α and Mx transcript abundance in gull lymphocytes, with peak levels at 48 h post-infection (p < 0.01). In chicken embryos, recombinant IFN-α was associated with higher embryo survival and lower NDV NP transcript abundance than recombinant Mx under the tested conditions. In DF-1 cells and primary gull lymphocytes, 0.25 mg/mL recombinant IFN-α was associated with reduced NDV NP transcript abundance, and morphological inspection suggested less severe cytopathic effects in DF-1 cells. IFN-α treatment was also accompanied by lower transcription of TLR7, MyD88, IRF7, and Mx compared with the NDV group at 48 h. These data support a role for gull IFN-α in limiting NDV-associated transcriptional responses in vitro, while further protein-level and infectious-virus assays are required to define the underlying mechanism. Full article

Japanese encephalitis virus (JEV) is a zoonotic pathogen. Infection in breeding boars triggers severe testicular inflammatory storms, resulting in testicular swelling, asthenospermia, oligozoospermia and even irreversible loss of reproductive capacity. Magnolol, a natural extract, exhibits remarkable anti-inflammatory and antioxidant activities. This study utilized swine testicular (ST) cells as an in vitro model to explore magnolol’s protective effects against JEV-mediated inflammation and its underlying mechanism. ST cells were infected with JEV at an MOI of 1 and treated with magnolol at 8, 12 and 16 μg/mL. We detected pro-inflammatory cytokine expression, performed 4D-FastDIA quantitative proteomics to screen differentially expressed proteins, verified key RIG-I and NF-κB cascade molecules at mRNA and protein levels, and tracked p65 nuclear translocation through immunofluorescence. The data showed that JEV significantly elevated TNF-α, IL-1β, IL-6, IL-8 and CCL5, while magnolol reduced these cytokines in a dose-dependent manner. JEV reshaped the proteome of innate immunity and inflammation, and excessively activated the RIG-I/NF-κB axis to increase IKKβ, TRAF2, TRAF6 transcription and p65 phosphorylation and nuclear import; 24 h treatment with 16 μg/mL magnolol greatly restrained this overactivation. In summary, magnolol alleviates JEV-triggered inflammatory injury by inhibiting the RIG-I/NF-κB pathway, offering experimental evidence for its use as a natural agent to mitigate JEV-induced cellular inflammatory response in boars. Full article

The gut–lung axis is one of the bidirectional mucosal communication networks linking intestinal microbiota, microbial metabolites, immune regulation, and respiratory inflammation. This narrative review summarizes mechanistic and translational evidence identified through a structured but non-systematic search. This review focuses on gut-to-lung mechanisms, including immune cell trafficking, epithelial barrier regulation, and the role of gut microbiota and its metabolites. Among these metabolites, short-chain fatty acids (SCFAs), particularly acetate, propionate, and butyrate, are key mediators of interorgan communication and are mainly produced through microbial fermentation of dietary fibers and polysaccharides. Unlike previous reviews, reverse lung-to-gut mechanisms are also discussed, whereby respiratory infection, smoking, and lung injury may disrupt intestinal barrier integrity, alter gut microbiota composition, and promote intestinal immune dysregulation. Among plant-derived interventions, dietary fibers, polysaccharides, and polyphenols appear promising, mainly through SCFA-dependent immune modulation, enrichment of metabolite-producing bacteria, and subsequent suppression of inflammatory pathways. Some compounds may also act through microbiota-independent mechanisms, including direct antioxidant effects, epithelial barrier protection, and inhibition of inflammatory signaling pathways. Overall, SCFA-mediated immune regulation is the best-supported mechanism, whereas lung-to-gut signaling remains less established. Most evidence remains preclinical, highlighting the need for standardized human studies evaluating dose, safety, and clinically meaningful respiratory outcomes. Full article

The human immune system executes immune defense against foreign antigens, immune surveillance against mutant cells, and immune homeostasis to maintain bodily physiological equilibrium. Transfer RNA (tRNA) is an important part of gene expression regulation. Recent studies have found that aberrant tRNA modifications can disturb the function of the immune system by altering translation efficiency, including regulating immune recognition and signal transduction, as well as influencing apoptosis and autophagy. tRNA modifications are also closely related to the development and occurrence of immune-related disorders such as infections, tumors, and autoimmune diseases. By integrating current research on immune-related tRNA modifications, this review systematically summarizes the mechanisms of tRNA modifications involved in three major immune functions and their relationship with related diseases, encompassing the direct regulation of immune cells and the indirect immune effects mediated through tissue or tumor cells. In addition, some tRNA modifications can also modulate immune responses by affecting tRNA cleavage and the consequent generation of tRNA-derived small RNAs (tsRNAs). Accordingly, this review outlines promising intervention targets and unresolved research bottlenecks, facilitating follow-up investigations into tRNA modification-dependent immune regulation and translational therapeutic research. Full article

Enterococcus faecalis is an important opportunistic pathogen associated with persistent oral infections, biofilm formation, and antimicrobial tolerance, which makes phages targeting this species of both therapeutic and evolutionary interest. Here, we describe the isolation and characterization of Abitsa, a novel lytic Enterococcus phage representing a new species within the genus Efquatrovirus. Abitsa formed small plaques and displayed siphovirus-like morphology. It showed an optimal multiplicity of infection of 0.01, a short latent period of 10 min and a burst size of 28 ± 5 virions per infected cell. The phage efficiently suppressed planktonic growth of E. faecalis over a broad multiplicity of infection (MOI) range and significantly disrupted pre-formed biofilms, with the strongest effect observed at MOI 0.1, resulting in an 82.14% reduction in biofilm biomass. Abitsa remained stable at pH 4–8, at 5–50 °C for 1 h, and in up to 75% chloroform, but exhibited a narrow host range, lysing only one additional clinical E. faecalis isolate among 34 tested enterococcal isolates. Genome analysis showed that Abitsa has a 41,581-bp linear genome lacking lysogeny-associated genes and represents a novel Efquatrovirus species. Comparative structural and phylogenetic analyses additionally supported mosaic evolution and extensive domain shuffling in receptor-binding and lysis-related proteins of Efquatrovirus-like phages. Together, these results identify Abitsa as a biologically unusual and evolutionarily informative lytic phage with antibiofilm activity. Full article

Most of the publications on Anisakis simplex (Rudolphi, 1809) focus upon systematic aspects and zoonotic risk but there is lack of detailed information on infection and cellular immune response of the gonads. The current investigation detected whether gonadal infection by A. simplex affects reproductive development and how Atlantic mackerel, Scomber scombrus (L.), responds immunologically. Thirty-four specimens out of 62 S. scombrus (55%) individuals had the larvae on or in the gonads, and live and calcified dead larvae often co-occurred. Nematode larvae were found in both mature and immature gonads. The intensity of infection varied from 1 to 31 nematodes per gonad (5.68 ± 5.53, mean ± standard deviation). In ovaries that harboured the nematode (inside the organ and in the mesenteries around it), in close vicinity to the larvae, mast cells (MCs), rodlet cells (RCs), macrophages, and macrophage aggregates (MAs) occurred. Fewer of the above cells were observed in the mesenteries of parasitized testes. In the gonads of infected fish, within the granulomas that surrounded the calcified and live larvae, putative epithelioid cells, fibroblasts, MCs, MAs and collagen fibres were present. The absence of a correlation between the intensity of infection and the host gonadosomatic index in female and male gonads might indicate that A. simplex larvae do not affect the production of gametes and gonad development in Atlantic mackerel. Our results suggest that localized encapsulation represents an effective tolerance strategy allowing parasite persistence while preserving host reproductive function. Full article

Chimeric antigen receptor T-cell (CAR-T) therapy has substantially improved outcomes for patients with B-cell-associated hematological malignancies. While acute and early toxicities are well characterized, late complications (LCs) remain poorly understood. This scoping review aimed to identify and map the existing evidence on LCs in adult patients with hematological malignancies treated with CAR-T products approved by the European Medicines Agency (EMA). PubMed, Web of Science, and the Cochrane Library were searched for primary studies published from 2018 onwards. We included studies of adult patients receiving EMA-approved CAR-T therapies targeting CD19 or CD269. LCs were defined as diagnosis-based adverse events occurring ≥12 months after CAR-T infusion. Of 7715 records identified, 261 studies underwent full-text screening and 18 met the inclusion criteria. LCs clustered mainly as infections and secondary malignancies (SMs). Non-relapse mortality was reported in seven studies, with infections and SMs frequently reported as causes when cause-of-death data were available. Future studies should place emphasis on long-term clinical events after CAR-T therapy to improve the management of LCs and ultimately support better long-term outcomes for patients. Full article

Human skin is a complex organ whose functions depend on coordinated interactions between the epidermal and stromal layers. Reproducing this architecture in vitro remains challenging, as existing human models reproduce a restricted subset of the structural and functional features inherent to native tissue. Here, we describe a fibrin-based, multicellular human skin equivalent (HSE) composed of primary human keratinocytes, fibroblasts, preadipocytes, and endothelial cells organized into epidermal and stromal compartments. The resulting constructs achieved mature epidermal stratification with appropriate phenotypic markers, developed robust barrier properties, underwent spontaneous endothelial network assembly, and exhibited transcriptional profiles consistent with native skin. Optimized culture conditions supported long-term structural and functional stability through 42 days, maintaining a proliferative basal cell layer and intact epidermal architecture. Non-destructive optical coherence tomography enabled longitudinal monitoring of epidermal growth, providing a practical method for real-time quality assessment. To evaluate their utility for disease modeling, HSEs were challenged with cowpox virus to model infection by a classic dermotropic virus. Infected HSEs reproduced classic epithelial pathologies of human orthopoxvirus infection and exhibited dose-dependent suppression of host interferon signaling pathways, recapitulating known viral immune-evasion mechanisms. Together, these findings establish the vascularized, adipose-integrated HSE as a platform for long-term studies of human skin biology, host–pathogen dynamics, and therapeutic development. Full article

Equine piroplasmosis, caused by the intraerythrocytic protozoan Theileria equi, is a globally distributed tick-borne disease characterized by persistent infection and variable clinical manifestations. Although oxidative stress has been implicated in the pathogenesis of several hemoprotozoan diseases, information regarding redox imbalance and its relationship with inflammatory responses in horses naturally infected with T. equi remains limited. This study aimed to evaluate oxidative stress, antioxidant status, inflammatory cytokines, and clinicopathological alterations in horses naturally infected with T. equi. Thirty-five horses naturally infected with T. equi and twenty clinically healthy horses were enrolled. Infection was confirmed by clinical evaluation, hematological and biochemical analyses, an indirect fluorescent antibody test, and polymerase chain reaction. Serum concentrations of interferon-gamma, tumor necrosis factor-alpha, reduced glutathione, and malondialdehyde were assayed. Infected horses showed significantly lower platelet counts and significantly higher serum activities of aspartate aminotransferase than controls. Serum interferon-gamma and tumor necrosis factor concentrations were significantly increased, indicating persistent inflammatory activation. Infected horses also exhibited significantly higher malondialdehyde concentrations and lower reduced glutathione levels, consistent with enhanced lipid peroxidation and impaired antioxidant defenses. Correlation analyses revealed a negative association between reduced glutathione and white blood cell count and between malondialdehyde and red blood cell count, whereas malondialdehyde concentrations were positively associated with clinical score. Chronic T. equi infection is associated with oxidative stress, depletion of antioxidant defenses, and sustained inflammatory responses. The interaction between oxidative stress and inflammation may contribute to hematological abnormalities and disease expression. Full article

Fragrant pear canker, caused by Cytospora pyri, is a major branch disease that reduces the productivity and longevity of Korla fragrant pear orchards in Xinjiang, China. During infection and lesion expansion in woody tissues, C. pyri must breach the host cell wall barrier, in which pectin degradation plays a central role by weakening intercellular adhesion and disrupting tissue integrity. Members of glycoside hydrolase family 28 (GH28), represented mainly by polygalacturonases and other pectin-degrading enzymes, are closely involved in fungal invasion and colonization. However, the composition and virulence-related functions of this gene family encoding for these enzymes in C. pyri remain unclear. In this study, GH28 genes were systematically identified and comparatively analyzed in C. pyri and closely related Cytospora species. Infection-stage expression profiling and functional validation were then performed to assess their roles in pathogenicity. A total of 73 GH28 genes were identified across five Cytospora species, including 15 in C. pyri. Most C. pyri GH28 proteins were predicted to be acidic, hydrophilic, extracellularly secreted proteins carrying conserved motifs. Phylogenetic analysis showed that C. pyri GH28 members were closely related to homologs from C. mali. Genomic distribution analysis revealed that these genes were dispersed across multiple scaffolds, with no obvious tandem duplication events. RT-qPCR analysis showed that all seven candidate GH28 genes were induced during infection of fragrant pear branches, with VP1G_08835 and VP1G_03209 exhibiting strong expression responses at 6 dpi. Functional validation further showed that deletion of VP1G_08835 impaired vegetative growth and reduced lesion length on detached pear branches by 26.62% compared with the wild type, whereas complementation restored these phenotypes. These findings demonstrate that GH28 genes participate in C. pyri infection and identify VP1G_08835 as an important GH28 member required for normal growth and contributing to virulence. Full article