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Keywords = immunological characteristics

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16 pages, 1039 KiB  
Article
PROX1 Expression in Resected Non-Small Cell Lung Cancer: Immunohistochemical Profile and Clinicopathological Correlates
by Evangelia Ntikoudi, Thomas Karagkounis, Konstantinos S. Mylonas, Stylianos Kykalos, Dimitrios Schizas, Ioannis N. Vamvakaris, Ekaterini Politi, Michail V. Karamouzis and Stamatios Theocharis
Med. Sci. 2025, 13(3), 140; https://doi.org/10.3390/medsci13030140 (registering DOI) - 17 Aug 2025
Abstract
Background/Objectives: PROX1 (prospero homeobox 1) is a transcription factor involved in lymphangiogenesis and cellular differentiation. Its role in cancer biology appears to be highly context-dependent, with it exhibiting both tumor-promoting and -suppressive functions across various malignancies. Nonetheless, the clinical significance of PROX1 expression [...] Read more.
Background/Objectives: PROX1 (prospero homeobox 1) is a transcription factor involved in lymphangiogenesis and cellular differentiation. Its role in cancer biology appears to be highly context-dependent, with it exhibiting both tumor-promoting and -suppressive functions across various malignancies. Nonetheless, the clinical significance of PROX1 expression in non-small cell lung cancer (NSCLC) remains poorly elucidated. The objective of this study is to evaluate the immunohistochemical expression of PROX1 in NSCLC, specifically in the adenocarcinoma and squamous cell carcinoma subtypes, and to assess its correlation with clinicopathologic features and overall survival (OS). Methods: This retrospective study included surgically resected specimens from 121 patients with histologically confirmed NSCLC. PROX1 expression was assessed via immunohistochemistry on formalin-fixed, paraffin-embedded specimens. Staining intensity (graded 0– National and Kapodistrian University of Athens 3) and the percentage of positive tumor cells were recorded. Correlations with histological subtype, tumor characteristics, and OS were analyzed using chi-square tests, one-way ANOVA, and Kaplan–Meier survival analysis with log-rank testing. Results: Low PROX1 intensity (level 1) was significantly associated with P63 positivity (p = 0.028), while high PROX1 intensity (level 3) correlated with nodal metastasis to station 3 (S3+) (p = 0.025). Additionally, alveolar-pattern adenocarcinomas exhibited intermediate PROX1 expression (26–50%) (p = 0.010). Although PROX1 positivity did not differ among mucinous and non-mucinous adenocarcinomas (p = 0.152), its distribution across defined expression subgroups was statistically significant (p = 0.002). Tumors with low PROX1 expression (0–24%) were associated with a larger maximum tumor diameter (p = 0.026). PROX1 expression was not independently associated with OS (p > 0.05). Factors significantly associated with improved survival included an age < 50 years, female sex, the absence of necrosis, fewer than 10 positive lymph nodes, a lymph node ratio < 0.5, and the absence of extensive nodal involvement in stations 5, 10, 11, and 12. Conclusions: Although PROX1 expression is variably associated with specific histologic subtypes and nodal metastases in NSCLC, it does not independently predict overall survival. Its expression patterns suggest a potential role in tumor differentiation and lymphatic spread. Further mechanistic and immunologic studies are warranted to elucidate the functional significance of PROX1 in lung cancer biology. Full article
(This article belongs to the Section Cancer and Cancer-Related Research)
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20 pages, 633 KiB  
Review
Food Protein-Induced Enterocolitis Syndrome Across Lifespan: Focus on Adolescence
by Marta Barbato, Mariannita Gelsomino, Giulia Bersani, Francesco Mastellone, Valentina Giorgio, Ludovica Iezzi, Rosa Buonagura, Cristiano Caruso, Stefano Miceli Sopo and Angela Rizzi
J. Clin. Med. 2025, 14(16), 5799; https://doi.org/10.3390/jcm14165799 (registering DOI) - 16 Aug 2025
Abstract
Background/Objectives: Food protein-induced enterocolitis syndrome (FPIES) is a food-related hypersensitivity disorder characterized by delayed repeated vomiting that typically presents within the first years of life. Although FPIES has traditionally been considered a pediatric condition, it has more recently been observed also in teenagers [...] Read more.
Background/Objectives: Food protein-induced enterocolitis syndrome (FPIES) is a food-related hypersensitivity disorder characterized by delayed repeated vomiting that typically presents within the first years of life. Although FPIES has traditionally been considered a pediatric condition, it has more recently been observed also in teenagers and adults. Adult FPIES may be a continuation of childhood-onset disease or new-onset forms developing later in life. This review aims to describe the peculiarities of FPIES across the lifespan and to provide an update from the last years on the studies focused on FPIES in adolescence. Methods: Papers focusing on FPIES in adolescents, in English and published in PubMed, were reviewed. Results: There is less data available in the literature on FPIES in adolescents. Multiple sensitizations to food can compromise nutritional status in patients with FPIES. Several potential diagnostic biomarkers related to genomic susceptibility, altered immunologic response, mucosal inflammation and intestinal microbiota are under study/validation. The lack of age-specific diagnostic algorithms makes it difficult to understand the clinical features of persistent forms of FPIES. Conclusions: Shared transition medicine protocols tailored to adolescents could help us better understand the clinical, pathophysiological, diagnostic, and therapeutic characteristics of this delicate phase of life. Full article
(This article belongs to the Special Issue Allergic Diseases Across the Lifespan: From Infancy to Old Age)
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34 pages, 1198 KiB  
Article
Safety Considerations for Natural Products with Adaptogenic and Immunomodulating Activities
by Chen Jia Wen Liang, Herman J. Woerdenbag, Corine Ekhart, Annabella Vitalone and Florence P. A. M. van Hunsel
Pharmaceuticals 2025, 18(8), 1208; https://doi.org/10.3390/ph18081208 - 15 Aug 2025
Abstract
Background/Objectives: Natural products with claimed adaptogenic and/or immunomodulatory effects are widely used in traditional medicine systems across Eurasia. These include herbal remedies (e.g., Panax ginseng), fungi (e.g., Ganoderma lucidum), and animal-derived substances (e.g., propolis from Apis mellifera). Despite their [...] Read more.
Background/Objectives: Natural products with claimed adaptogenic and/or immunomodulatory effects are widely used in traditional medicine systems across Eurasia. These include herbal remedies (e.g., Panax ginseng), fungi (e.g., Ganoderma lucidum), and animal-derived substances (e.g., propolis from Apis mellifera). Despite their popularity, the safety profiles of these products—particularly concerning adverse events (AEs) and serious adverse events (SAEs)—remain insufficiently understood. This study aimed to assess the safety profiles of adaptogenic and immunomodulatory natural products through a scoping review of published human studies and an analysis of individual case safety reports (ICSRs) from the WHO-UMC VigiBase database. Methods: A scoping review was conducted using PubMed (1980–2024) in line with PRISMA-ScR guidelines. Eligible studies included randomized and non-randomized clinical trials and case reports in humans focused on safety outcomes. Data extraction followed the Joanna Briggs Institute (JBI) standardized template. ICSRs from VigiBase were analyzed by product type, AE type and seriousness, and demographic characteristics. The data were further organized to highlight the 15 most frequently reported products and their top five System Organ Classes (SOCs) and Preferred Terms (PTs). Results: The scoping review identified 51 natural products with reported adaptogenic and/or immunomodulatory properties. This included 285 clinical trials and 119 case studies on single-ingredient products and 54 clinical trials and 21 case studies on multi-ingredient preparations. Common AEs included gastrointestinal, dermatological, hepatic, cardiovascular, and immunological reactions. SAEs were rare but reported for Echinacea purpurea, Silybum marianum, and Camellia sinensis. From Vigibase, 45,042 ICSRs were retrieved for 49 natural products: 10,702 for single-ingredient and 34,340 for multi-ingredient products. Among 7856 reports listing a single-ingredient product as the sole suspect, 15.8% were SAEs, including eight fatal cases. However, the causality remained unclear due to insufficient data. Ganoderma lucidum, Viscum album, and Silybum marianum were most frequently associated with SAEs. In multi-ingredient products, propolis was frequently linked to hypersensitivity and skin reactions. Conclusions: This study provides a comprehensive overview of the safety profiles of adaptogenic and immunomodulatory natural products. Variability in product composition, lack of standardization, incomplete reporting in clinical studies, and underreporting in pharmacovigilance databases complicate accurate risk assessment. For multi-ingredient products, attributing specific AEs to specific components remains difficult. Further high-quality clinical research and improved pharmacovigilance are needed, along with clear safety warnings to reduce risks for consumers. Full article
11 pages, 443 KiB  
Article
Cognitive Screening with the Italian International HIV Dementia Scale in People Living with HIV: A Cross-Sectional Study in the cART Era
by Maristella Belfiori, Francesco Salis, Sergio Angioni, Claudia Bonalumi, Diva Cabeccia, Camilla Onnis, Nicola Pirisi, Francesco Ortu, Paola Piano, Stefano Del Giacco and Antonella Mandas
Infect. Dis. Rep. 2025, 17(4), 95; https://doi.org/10.3390/idr17040095 - 6 Aug 2025
Viewed by 158
Abstract
Background: HIV-associated neurocognitive disorders (HANDs) continue to be a significant concern, despite the advancements in prognosis achieved through Combination Antiretroviral Therapy (cART). Neuropsychological assessment, recommended by international guidelines for HANDs diagnosis, can be resource-intensive. Brief screening tools, like the International HIV Dementia [...] Read more.
Background: HIV-associated neurocognitive disorders (HANDs) continue to be a significant concern, despite the advancements in prognosis achieved through Combination Antiretroviral Therapy (cART). Neuropsychological assessment, recommended by international guidelines for HANDs diagnosis, can be resource-intensive. Brief screening tools, like the International HIV Dementia Scale (IHDS) and the Montreal Cognitive Assessment (MoCA), are crucial in facilitating initial evaluations. This study aims to assess the Italian IHDS (IHDS-IT) and evaluate its sensitivity and specificity in detecting cognitive impairment in HIV patients. Methods: This cross-sectional study involved 294 patients aged ≥30 years, evaluated at the Immunology Unit of the University of Cagliari. Cognitive function was assessed using the MoCA and IHDS. Laboratory parameters, such as CD4 nadir, current CD4 count, and HIV-RNA levels, were also collected. Statistical analyses included Spearman’s correlation, Receiver Operating Characteristic analysis, and the Youden J statistic to identify the optimal IHDS-IT cut-off for cognitive impairment detection. Results: The IHDS and MoCA scores showed a moderate positive correlation (Spearman’s rho = 0.411, p < 0.0001). ROC analysis identified an IHDS-IT cut-off of ≤9, yielding an Area Under the Curve (AUC) of 0.76, sensitivity of 71.7%, and specificity of 67.2%. At this threshold, 73.1% of patients with MoCA scores below 23 also presented abnormal IHDS scores, highlighting the complementary utility of both cognitive assessment instruments. Conclusions: The IHDS-IT exhibited fair diagnostic accuracy for intercepting cognitive impairment, with a lower optimal cut-off than previously reported. The observed differences may reflect this study cohort’s demographic and clinical characteristics, including advanced age and long-lasting HIV infection. Further, longitudinal studies are necessary to validate these findings and to confirm the proposed IHDS cut-off over extended periods. Full article
(This article belongs to the Section HIV-AIDS)
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17 pages, 1788 KiB  
Article
Impact of Major Pelvic Ganglion Denervation on Prostate Histology, Immune Response, and Serum Prolactin and Testosterone Levels in Rats
by Pabeli Saraí Becerra-Romero, Cynthia Fernández-Pomares, Juan Carlos Rodríguez-Alba, Jorge Manzo, Gonzalo E. Aranda-Abreu, Fausto Rojas-Durán, Deissy Herrera-Covarrubias, María Rebeca Toledo-Cárdenas, Genaro Alfonso Coria-Ávila and Maria Elena Hernández-Aguilar
Immuno 2025, 5(3), 33; https://doi.org/10.3390/immuno5030033 - 6 Aug 2025
Viewed by 337
Abstract
The prostate gland, a male accessory reproductive organ, is regulated by hormonal inputs and autonomic innervation from the major pelvic ganglion. This study examined the effects of major pelvic ganglion denervation on prostate histology, immune cell infiltration, and systemic levels of prolactin, testosterone, [...] Read more.
The prostate gland, a male accessory reproductive organ, is regulated by hormonal inputs and autonomic innervation from the major pelvic ganglion. This study examined the effects of major pelvic ganglion denervation on prostate histology, immune cell infiltration, and systemic levels of prolactin, testosterone, and cytokines in rats. Male Wistar rats (300–350 g) were divided into groups receiving bilateral axotomy of the hypogastric nerve, the pelvic nerve, or both, alongside with a sham-operated control. After 15 days, the animals were killed, and prostate tissue was dissociated in DMEM medium containing DNase I and collagenase. The dissociated cells were stained with fluorochrome-conjugated antibodies, and cell characterization was performed using a flow cytometer. Hematoxylin and eosin (H&E) staining was used to analyze histological characteristics, while testosterone, prolactin, and interleukin levels were measured via ELISA. Histological analysis revealed inflammatory atypical hypertrophy e hiperplasia. Immunological assessments demonstrated increased leukocytes, T lymphocytes (CD4+ and CD8+), B lymphocytes, and macrophages following double nerve axotomy. Serum analyses showed elevated pro-inflammatory cytokines IL-1β, IL-6, and IFN-γ, as well as anti-inflammatory IL-10, in denervated animals. Hormonal assessments revealed significant increases in serum prolactin and testosterone levels after double axotomy. Loss of neural control may promote pathological prostate changes via inflammation and hormonal dysregulation, offering insights into neuroimmune and neuroendocrine mechanisms underlying prostate pathologies. Full article
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10 pages, 594 KiB  
Article
Perspectives of Physiotherapists on Immune Functioning in Oncological Rehabilitation in the Netherlands: Insights from a Qualitative Study
by Anne M. S. de Hoop, Karin Jäger, Jaap J. Dronkers, Cindy Veenhof, Jelle P. Ruurda, Cyrille A. M. Krul, Raymond H. H. Pieters and Karin Valkenet
Appl. Sci. 2025, 15(15), 8673; https://doi.org/10.3390/app15158673 - 5 Aug 2025
Viewed by 285
Abstract
Oncology physiotherapists frequently provide care for patients experiencing severe immunosuppression. Exercise immunology, the science that studies the effects of exercise on the immune system, is a rapidly evolving field with direct relevance to oncology physiotherapists. Understanding oncology physiotherapists’ perspectives on the subject of [...] Read more.
Oncology physiotherapists frequently provide care for patients experiencing severe immunosuppression. Exercise immunology, the science that studies the effects of exercise on the immune system, is a rapidly evolving field with direct relevance to oncology physiotherapists. Understanding oncology physiotherapists’ perspectives on the subject of immune functioning is essential to explore its possible integration into clinical reasoning. This study aimed to assess the perspectives of oncology physiotherapists concerning immune functioning in oncology physiotherapy. For this qualitative research, semi-structured interviews were performed with Dutch oncology physiotherapists. Results were analyzed via inductive thematic analysis, followed by a validation step with participants. Fifteen interviews were performed. Participants’ ages ranged from 30 to 63 years. Emerging themes were (1) the construct ‘immune functioning’ (definition, and associations with this construct in oncology physiotherapy), (2) characteristics related to decreased immune functioning (in oncology physiotherapy), (3) negative and positive influences on immune functioning (in oncology physiotherapy), (4) tailored physiotherapy treatment, (5) treatment outcomes in oncology physiotherapy, (6) the oncology physiotherapist within cancer care, and (7) measurement and interpretation of immune functioning. In conclusion, oncology physiotherapists play an important role in the personalized and comprehensive care of patients with cancer. They are eager to learn more about immune functioning with the goal of better informing patients about the health effects of exercise and to tailor their training better. Future exercise-immunology research should clarify the effects of different exercise modalities on immune functioning, and how physiotherapists could evaluate these effects. Full article
(This article belongs to the Special Issue Novel Approaches of Physical Therapy-Based Rehabilitation)
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10 pages, 254 KiB  
Article
Lupus Anticoagulant Positivity as a Risk Marker for Hemolytic Anemia in Patients with APS
by Ji-Hyoun Kang
Medicina 2025, 61(8), 1364; https://doi.org/10.3390/medicina61081364 - 28 Jul 2025
Viewed by 342
Abstract
Background and Objectives: Thrombocytopenia and hemolytic anemia are common but non-criteria manifestations of antiphospholipid syndrome (APS). However, their relationship with specific immunological profiles remains poorly characterized. This study aimed to evaluate these hematologic manifestations and identify their serological associations in patients with [...] Read more.
Background and Objectives: Thrombocytopenia and hemolytic anemia are common but non-criteria manifestations of antiphospholipid syndrome (APS). However, their relationship with specific immunological profiles remains poorly characterized. This study aimed to evaluate these hematologic manifestations and identify their serological associations in patients with APS. Materials and Methods: We retrospectively reviewed 346 patients diagnosed with APS. Demographic, clinical, and laboratory characteristics were analyzed. Logistic regression was used to identify risk factors associated with hemolytic anemia. Results: The mean age was 47.1 ± 13.1 years, and 71.7% were female. Thrombocytopenia was present in 34.5%, and hemolytic anemia in 16.5% of patients. Lupus anticoagulant (LAC) was the most common antibody (66.8%). In univariate analysis, hemolytic anemia was significantly associated with LAC positivity (OR 4.216, 95% CI: 2.326–7.640, p < 0.001), anticardiolipin IgG (OR 7.170, p = 0.007), triple positivity (OR 3.638, p = 0.002), and diabetes mellitus (OR 2.084, p = 0.007). DIAPS showed a protective trend (OR 0.547, p = 0.002). In multivariate analysis, only LAC remained an independent risk factor for hemolytic anemia (adjusted OR 3.557, 95% CI: 1.355–9.335, p = 0.003). Conclusions: LAC positivity is an independent predictor of hemolytic anemia in APS. These findings suggest a distinct immunologic profile among patients with hematologic involvement and highlight the need for further investigation into non-criteria manifestations. Full article
(This article belongs to the Special Issue Autoimmune Diseases: Advances and Challenges)
22 pages, 1822 KiB  
Article
Increased Concentration of Anti-Egg Albumin Antibodies in Cerebrospinal Fluid and Serum of Patients with Alzheimer’s Disease—Discussion on Human Serpins’ Similarity and Probable Involvement in the Disease Mechanism
by Dionysia Amanatidou, Magdalini Tsolaki, Vasileios Fouskas, Ioannis Gavriilidis, Maria Myriouni, Anna Anastasiou, Efthimia Papageorgiou, Diona Porfyriadou, Zoi Parcharidi, Eleftheria Papasavva, Maria Fili and Phaedra Eleftheriou
Biomolecules 2025, 15(8), 1085; https://doi.org/10.3390/biom15081085 - 27 Jul 2025
Viewed by 570
Abstract
Alzheimer’s Disease (AD) is a multifactorial process. Amyloid plaque formation constitutes the main characteristic of the disease. Despite the identification of numerous factors associated with AD, the mechanism remains unclear in several aspects. Disturbances in intestinal and blood–brain barrier (BBB) penetration, observed in [...] Read more.
Alzheimer’s Disease (AD) is a multifactorial process. Amyloid plaque formation constitutes the main characteristic of the disease. Despite the identification of numerous factors associated with AD, the mechanism remains unclear in several aspects. Disturbances in intestinal and blood–brain barrier (BBB) penetration, observed in AD, may facilitate immunologic response to food-derived antigens. In the present study, antibodies against egg albumin, bovine-casein, and N-Glycolyl-Neuraminic acid (Neu5Gc) were measured in the cerebrospinal fluid (CSF) and serum of the patients using an enzyme-linked immunosorbent assay (ELISA). Zero anti-Neu5Gc and low concentrations of anti-casein antibodies were detected. Increased anti-native egg albumin antibodies were present in the serum of patients of all stages with 65% positivity (p < 0.001) in mild disease and a higher percentage in females (81.9%, p < 0.001). Lower serum positivity to anti-denatured egg albumin antibodies was observed, showing a gradual increase with severity and higher prevalence also in females. In the CSF, anti-native and anti-denatured egg albumin antibodies were mainly observed in severely ill patients with accumulative positivity to either antigen, reaching 61.8% in severe vs. 15% in mild disease (p < 0.001). Increased values were mainly observed in males. Anti-egg albumin antibodies may be implicated in the disease mechanism through sequence/structural similarity with human proteins, mainly serpins, and it would be worth consideration in further investigations and therapeutic strategies. Full article
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12 pages, 1316 KiB  
Article
Retinal Epithelial Neutralization Assay Optimizes AAV Serotype Selection for Ocular Gene Therapy
by Yao Li, Yujia Chen, Nan Huo, Zuyuan Jia, He Huang, Zhenghao Zhao, Shipo Wu and Lihua Hou
Viruses 2025, 17(7), 988; https://doi.org/10.3390/v17070988 - 15 Jul 2025
Viewed by 436
Abstract
Adeno-associated virus (AAV) vectors face a critical translational challenge in ocular gene therapy due to pre-existing neutralizing antibodies (NAbs) whose seroprevalence limits patient eligibility. Standard NAb detection using non-ocular cell models (Human Embryonic Kidney 293T) may inadequately predict retinal transduction inhibition due to [...] Read more.
Adeno-associated virus (AAV) vectors face a critical translational challenge in ocular gene therapy due to pre-existing neutralizing antibodies (NAbs) whose seroprevalence limits patient eligibility. Standard NAb detection using non-ocular cell models (Human Embryonic Kidney 293T) may inadequately predict retinal transduction inhibition due to cell type-related variations in receptor usage and immunogenicity. This study established parallel NAb detection platforms utilizing human retinal pigment epithelial (ARPE-19) cells and standard 293T cells to systematically evaluate clinical serum samples against ophthalmologically relevant AAV serotypes (2, 5, 8, 9) via luciferase reporter-based transduction inhibition assays. Comparative analysis demonstrated ARPE-19 exhibited 42–48% higher NAb titers against AAV5/9 compared to 293T cells, with distinct serotype-biased neutralization hierarchies observed between cellular models. Furthermore, female-derived sera exhibited significantly elevated NAbs against particular serotypes in the ARPE-19 system. Critically, inter-serotype cross-neutralization correlation patterns differed substantially between cellular platforms. These findings demonstrate that physiologically relevant retinal cellular models provide essential immunological profiling data, revealing NAb characteristics obscured in standard assays. Consequently, employing retinal cell-based platforms is crucial for optimizing AAV serotype selection, patient stratification, and predicting clinical outcomes in ocular gene therapy. Full article
(This article belongs to the Section General Virology)
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22 pages, 498 KiB  
Review
The XEC Variant: Genomic Evolution, Immune Evasion, and Public Health Implications
by Alaa A. A. Aljabali, Kenneth Lundstrom, Altijana Hromić-Jahjefendić, Nawal Abd El-Baky, Debaleena Nawn, Sk. Sarif Hassan, Alberto Rubio-Casillas, Elrashdy M. Redwan and Vladimir N. Uversky
Viruses 2025, 17(7), 985; https://doi.org/10.3390/v17070985 - 15 Jul 2025
Viewed by 963
Abstract
Narrative review synthesizes the most current literature on the SARS-CoV-2 XEC variant, focusing on its genomic evolution, immune evasion characteristics, epidemiological dynamics, and public health implications. To achieve this, we conducted a structured search of the literature of peer-reviewed articles, preprints, and official [...] Read more.
Narrative review synthesizes the most current literature on the SARS-CoV-2 XEC variant, focusing on its genomic evolution, immune evasion characteristics, epidemiological dynamics, and public health implications. To achieve this, we conducted a structured search of the literature of peer-reviewed articles, preprints, and official surveillance data from 2023 to early 2025, prioritizing virological, clinical, and immunological reports related to XEC and its parent lineages. Defined by the distinctive spike protein mutations, T22N and Q493E, XEC exhibits modest reductions in neutralization in vitro, although current evidence suggests that mRNA booster vaccines, including those targeting JN.1 and KP.2, retain cross-protective efficacy against symptomatic and severe disease. The XEC strain of SARS-CoV-2 has drawn particular attention due to its increasing prevalence in multiple regions and its potential to displace other Omicron subvariants, although direct evidence of enhanced replicative fitness is currently lacking. Preliminary analyses also indicated that glycosylation changes at the N-terminal domain enhance infectivity and immunological evasion, which is expected to underpin the increasing prevalence of XEC. The XEC variant, while still emerging, is marked by a unique recombination pattern and a set of spike protein mutations (T22N and Q493E) that collectively demonstrate increased immune evasion potential and epidemiological expansion across Europe and North America. Current evidence does not conclusively associate XEC with greater disease severity, although additional research is required to determine its clinical relevance. Key knowledge gaps include the precise role of recombination events in XEC evolution and the duration of cross-protective T-cell responses. New research priorities include genomic surveillance in undersampled regions, updated vaccine formulations against novel spike epitopes, and long-term longitudinal studies to monitor post-acute sequelae. These efforts can be augmented by computational modeling and the One Health approach, which combines human and veterinary sciences. Recent computational findings (GISAID, 2024) point to the potential of XEC for further mutations in under-surveilled reservoirs, enhancing containment challenges and risks. Addressing the potential risks associated with the XEC variant is expected to benefit from interdisciplinary coordination, particularly in regions where genomic surveillance indicates a measurable increase in prevalence. Full article
(This article belongs to the Special Issue Translational Research in Virology)
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17 pages, 2353 KiB  
Article
High TCR Degeneracy Enhances Antiviral Efficacy of HTLV-1-Specific CTLs by Targeting Variant Viruses in HAM Patients
by Ryuji Kubota, Kousuke Hanada, Mineki Saito, Mika Dozono, Satoshi Nozuma and Hiroshi Takashima
Int. J. Mol. Sci. 2025, 26(14), 6602; https://doi.org/10.3390/ijms26146602 - 10 Jul 2025
Viewed by 395
Abstract
T-cell receptors (TCRs) exhibit degeneracy, enabling individual TCRs to recognize multiple altered peptide ligands (APLs) derived from a single cognate antigen. This characteristic has been involved in the pathogenesis of autoimmune diseases through cross-reactivity between microbial and self-antigens. Cytotoxic T lymphocytes (CTLs), which [...] Read more.
T-cell receptors (TCRs) exhibit degeneracy, enabling individual TCRs to recognize multiple altered peptide ligands (APLs) derived from a single cognate antigen. This characteristic has been involved in the pathogenesis of autoimmune diseases through cross-reactivity between microbial and self-antigens. Cytotoxic T lymphocytes (CTLs), which recognize peptide–MHC class I complexes via TCRs, play a critical role in the immune response against viral infections. However, the extent to which TCR degeneracy within a population of virus-specific CTLs contributes to effective viral control remains poorly understood. In this study, we investigated the magnitude and functional relevance of TCR degeneracy in CTLs targeting an immunodominant epitope of human T-cell leukemia virus type 1 (HTLV-1) in patients with HTLV-1-associated myelopathy (HAM). Using peripheral blood mononuclear cells (PBMCs) from these patients, we quantified TCR degeneracy at the population level by comparing CTL responses to a panel of APLs with responses to the cognate epitope. Our findings demonstrated that increased TCR degeneracy, particularly at the primary TCR contact residue at position 5 of the antigen, was inversely correlated with HTLV-1 proviral load (p = 0.038, R = −0.40), despite similar functional avidity across patient-derived CTLs. Viral sequencing further revealed that CTLs with high TCR degeneracy exerted stronger selective pressure on the virus, as indicated by a higher frequency of nonsynonymous substitutions within the epitope-encoding region in patients with highly degenerate TCR repertoires. Moreover, TCR degeneracy was positively correlated with the recognition rate of epitope variants (p = 0.018, R = 0.76), suggesting that CTLs with high TCR degeneracy exhibited enhanced recognition of naturally occurring epitope variants compared to those with low TCR degeneracy. Taken together, these results suggest that virus-specific CTLs with high TCR degeneracy possess superior antiviral capacity, characterized by broadened epitope recognition and more effective suppression of HTLV-1 infection. To our knowledge, this is the first study to systematically quantify TCR degeneracy in HTLV-1-specific CTLs and evaluate its contribution to viral control in HAM patients. These findings establish TCR degeneracy as a critical determinant of antiviral efficacy and provide a novel immunological insight into the mechanisms of viral suppression in chronic HTLV-1 infection. Full article
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19 pages, 10921 KiB  
Article
Stratification of Hepatocellular Carcinoma Using N6-Methyladenosine
by Nan Wang, Jia-Xin Shi, Matthias Bartneck, Edgar Dahl and Junqing Wang
Cancers 2025, 17(13), 2220; https://doi.org/10.3390/cancers17132220 - 2 Jul 2025
Viewed by 467
Abstract
Background: The N6-methyladenosine (m6A) modification of eukaryotic mRNA is the most prevalent of such epigenetic modifications and has recently been identified as a potential player in the pathogenesis and progression of hepatocellular carcinoma (HCC). With the increasing emergence [...] Read more.
Background: The N6-methyladenosine (m6A) modification of eukaryotic mRNA is the most prevalent of such epigenetic modifications and has recently been identified as a potential player in the pathogenesis and progression of hepatocellular carcinoma (HCC). With the increasing emergence of immunotherapy in the treatment of HCC, we have evaluated the potential of m6A-related genes in predicting overall survival and the therapeutic efficacy of immunotherapy in HCC patients. Methods: We employed transcriptomic data from TCGA-LIHC and GSE76427, comprising a total of 485 HCC patients, as the training set. Based on 23 recognized m6A regulators, we performed clustering analysis on HCC patients. The intersecting differentially expressed genes (DEGs) among subtypes were used in least absolute shrinkage and selection operator (LASSO) Cox and multivariate Cox regression analyses to construct the risk model. For the quantification of a risk model of HCC patients, a risk score was developed and correlated with clinical and immunological parameters. Furthermore, a single-cell transcriptomic atlas was used to analyze the relationship between model genes and immune cell subpopulations. Mechanistic studies included in vitro assays to validate the association between the m6A-related gene ANLN and the progression of HCC. Results: Internal (TCGA and GEO) and external validation (ICGC) suggested that an 8-gene risk score provides an accurate and stable prognostic assessment for HCC. Furthermore, the high-risk score, characterized by elevated TP53 mutation frequency, tumor mutation burden (TMB), and tumor stem cell characteristics indicated a poor prognosis. The prognostic signature was associated with immune cell infiltration in HCC. Those patients with a high-risk score had lower immune tolerance with a better prediction of the efficacy of immunotherapy. The risk model helps to assess and predict the response and prognosis of HCC patients to immune checkpoint inhibitors (ICIs). Additionally, single-cell RNA sequencing data revealed that the high-risk group had a higher proportion of T cells and fewer immunosuppressive T cells, potentially correlating with a better response to immunotherapy. Finally, in vitro experiments showed that ANLN, an m6A-related gene, promoted the proliferation and migration of HCC cells. Conclusions: In this study, we identified and validated an m6A gene signature consisting of eight genes that can be used to predict prognosis and immunotherapy efficacy in HCC patients. Full article
(This article belongs to the Section Cancer Immunology and Immunotherapy)
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16 pages, 456 KiB  
Review
Clinical and Epidemiological Features and Antimicrobial Susceptibility Patterns of Chryseobacterium Species: A Scoping Review
by Chienhsiu Huang
Medicina 2025, 61(7), 1197; https://doi.org/10.3390/medicina61071197 - 30 Jun 2025
Viewed by 415
Abstract
Background and Objectives: Infections with Chryseobacterium species are rare, and the susceptibility patterns of these species to antimicrobial agents are unclear. Therefore, the aim of this study was to explore the clinical and epidemiological features and antimicrobial susceptibility patterns of Chryseobacterium species by [...] Read more.
Background and Objectives: Infections with Chryseobacterium species are rare, and the susceptibility patterns of these species to antimicrobial agents are unclear. Therefore, the aim of this study was to explore the clinical and epidemiological features and antimicrobial susceptibility patterns of Chryseobacterium species by reviewing previous research on the antibiograms of Chryseobacterium species and the illnesses caused by Chryseobacterium species. Materials and Methods: A comprehensive search of the PubMed and Web of Science databases was conducted for all studies that investigated antimicrobial susceptibility patterns of Chryseobacterium species published between January 1990 and February 2025. An extensive review of the infection incidences, isolation sites, clinical characteristics, and antimicrobial susceptibility patterns for infections caused by Chryseobacterium species was performed. Results: Several studies have revealed that the incidence of Chryseobacterium species infections is increasing, particularly in patients with comorbid conditions, mainly cardiovascular disease, diabetes mellitus, and malignancy. Most patients were elderly individuals, and most related illnesses were acquired in hospitals. The number of patients who received inappropriate antimicrobial therapy outnumbered the number of those who died. Antibiotics had little effect on Chryseobacterium species infection outcomes. Sixteen studies were included in the current scoping review. The susceptibility rates of Chryseobacterium indologenes to piperacillin/tazobactam (2.9–100%), ciprofloxacin (4.34–85%), levofloxacin (8.69–100%), trimethoprim/sulfamethoxazole (33.3–100%), imipenem (0–33.3%), meropenem (0–38.8%), minocycline (30.4–100%), ceftazidime (0–100%), and cefepime (0–100%) varied. The susceptibility rates of Chryseobacterium gleum to piperacillin/tazobactam (0–33%), ciprofloxacin (21.4–40%), levofloxacin (59.5%), trimethoprim/sulfamethoxazole (57.1–93.3%), imipenem (0–2.4%), meropenem (0%), minocycline (83.3–100%), ceftazidime (0–23.8%), and cefepime (0–19.0%) varied. Conclusions: Morbidity and mortality due to the increasing incidence of Chryseobacterium species infections have considerably increased. Underlying immunological defenses and other clinical factors may influence the prognosis of Chryseobacterium species infection. Rather than bacterial virulence characteristics, host factors mostly affect patient outcomes. Most isolates of Chryseobacterium indologenes are susceptible to minocycline and trimethoprim/sulfamethoxazole. For the treatment of these infections, professional knowledge and therapeutic expertise must be integrated. Full article
(This article belongs to the Section Infectious Disease)
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17 pages, 623 KiB  
Review
A Review of Emerging Immunotherapeutic Strategies for IDH-Mutant Glioma
by Masih Tazhibi, Eric P. Grewal, Rishab Ramapriyan, Leland G. K. Richardson, Gust Vandecandelaere, Adrian Kalaw, Parker Kotlarz, Samuel J. Steuart, Jing Sun, Matthew Gaffey, Daniel P. Cahill, Julie J. Miller, William T. Curry and Bryan D. Choi
Cancers 2025, 17(13), 2178; https://doi.org/10.3390/cancers17132178 - 27 Jun 2025
Viewed by 919
Abstract
IDH-mutant gliomas (IMGs) are a unique subset of diffuse gliomas that follow a relatively indolent course compared to IDH-wildtype glioblastoma (GBM) but inevitably progress, often to a higher histologic grade. Current standard therapies, including surgery, chemoradiation, and the recently approved mutant IDH inhibitor [...] Read more.
IDH-mutant gliomas (IMGs) are a unique subset of diffuse gliomas that follow a relatively indolent course compared to IDH-wildtype glioblastoma (GBM) but inevitably progress, often to a higher histologic grade. Current standard therapies, including surgery, chemoradiation, and the recently approved mutant IDH inhibitor (mIDHi) vorasidenib, provide limited disease control and are not curative. Given the immunosuppressive tumor microenvironment (TME) driven by the mutant IDH enzyme and its associated oncometabolite 2-hydroxyglutarate (2-HG), novel immunotherapies offer a promising avenue for treatment. The goal of this paper is to review the main immunologic characteristics that distinguish IMG from GBM, including reduced T cell infiltration and function, fewer myeloid cells, and increased immune-dampening signaling. We also evaluate the preclinical and clinical evidence for immunotherapeutic approaches with the most potential to induce meaningful clinical activity, such as immune checkpoint inhibitors, CAR T cells, tumor vaccines, myeloid redirection, and oncolytic viruses. Despite significant advances in immunotherapy for IMG, fundamental questions persist, including optimal timing and combination strategies, mechanisms underpinning treatment resistance, and strategies to overcome the suppressive microenvironment. Future exploration of these treatment modalities, with a focus on mitigating soluble immunosuppressive factors in the TME, enhancing in situ T cell persistence, and leveraging novel antigen targets, is critical for advancing the state of therapy for this presently incurable group of tumors. Full article
(This article belongs to the Special Issue Emerging Research on Primary Brain Tumors)
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19 pages, 894 KiB  
Article
Serum IgE and IgA Levels in Pediatric Henoch–Schönlein Purpura: Clinical Characteristics and Immunological Correlations in the Context of Infectious Diseases—A Five-Year Retrospective Analysis
by Sînziana Oprițescu, Gabriela Viorela Nițescu, Mihaela Golumbeanu, Dora Boghițoiu, Elena Iuliana Ioniță, Monica Licu, Larisa-Marina-Elisabeth Chirigiu, Violeta Popovici, Loredana-Maria Marin and Elena Moroșan
Int. J. Mol. Sci. 2025, 26(13), 6053; https://doi.org/10.3390/ijms26136053 - 24 Jun 2025
Viewed by 563
Abstract
Immunoglobulin A vasculitis (IgAV), previously known as Henoch–Schönlein purpura (HSP), is a type of non-thrombocytopenic small-vessel vasculitis. HSP is the most common systemic vasculitis in pediatric patients, and it is characterized by purpura, arthritis or arthralgia, gastrointestinal pain, and renal dysfunction. This retrospective [...] Read more.
Immunoglobulin A vasculitis (IgAV), previously known as Henoch–Schönlein purpura (HSP), is a type of non-thrombocytopenic small-vessel vasculitis. HSP is the most common systemic vasculitis in pediatric patients, and it is characterized by purpura, arthritis or arthralgia, gastrointestinal pain, and renal dysfunction. This retrospective analysis also examines a range of demographic factors, including sex, geographic and environmental influences, age, and medication, to evaluate their potential effects on the pediatric population affected by HSP. The five-year hospital-based retrospective analysis included 138 hospitalized children diagnosed with HSP during hospitalization. Blood sample analysis was conducted to assess various immunological parameters, including levels of immunoglobulins (IgA and IgE), complement components (C3 and C4), C-reactive protein, fibrinogen, the erythrocyte sedimentation rate (ESR), and allergen panels. Elevated IgE levels and normal IgA serum concentrations were found to be strongly associated with infectious diseases in pediatric HSP patients. Patients with recurrent infectious diseases consistently exhibited elevated IgE levels and normal IgA levels during treatment despite no identified allergens, alongside an increased risk of disease recurrence. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma: 3rd Edition)
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