Search Results (992)

CXCL12 is a chemokine acting via CXCR4 that plays a key role in inflammatory processes by regulating leukocyte migration and immune responses, making it an important focus of research in neuroinfections. In this study, the CXCL12 chemokine was evaluated as a potential diagnostic marker of different neuroinfections with particular emphasis on tick-borne encephalitis (TBE). A group of 214 patients with confirmed meningitis and/or encephalitis was included and divided according to etiology into TBE, aseptic meningitis, neuroborreliosis, and purulent meningitis. CXCL12 concentration and other inflammatory parameters were measured in cerebrospinal fluid (CSF). CXCL12 levels were compared with those of controls (N = 25) and analyzed statistically. In addition, serum was used to determine albumin concentrations. CXCL12 concentrations were significantly higher in patients with neuroinfections compared to controls and showed good diagnostic performance in the overall study group (AUC = 0.791), with a more moderate diagnostic performance observed in individual etiological groups, except in the purulent meningitis group, where the effect was not statistically significant, likely due to the small sample size. CXCL12 also demonstrated some utility in differentiating between specific etiologies; however, this effect was limited. Better diagnostic performance was observed when CXCL12 was combined with pleocytosis in a composite model differentiating between the TBE group and aseptic meningitis (AUC = 0.761). The presented results indicate the role of CXCL12 in neuroinflammation while simultaneously highlighting its potential in the development of novel diagnostic approaches for viral neuroinfections. Despite higher levels in TBE, its standalone diagnostic value is limited; however, it may enhance diagnostic accuracy when combined with other markers such as pleocytosis. Full article

Background: Brain metastasis is associated with poor prognosis in lung adenocarcinoma (LUAD). Anoikis resistance may contribute to tumor cell survival during metastatic dissemination and brain colonization; however, robust biomarkers for prognostic stratification and brain metastasis-associated classification remain limited. This study aimed to investigate anoikis-related molecular features in LUAD brain metastasis and develop a machine learning-based signature for prognostic assessment and exploratory classification of primary and brain-metastatic LUAD samples. Methods: We integrated single-cell and multi-cohort bulk transcriptomic data. Single-cell analysis was performed to characterize anoikis-related cellular states and intercellular communication in primary and brain-metastatic LUAD samples. In the bulk transcriptomic analysis, TCGA-LUAD was used for prognostic feature selection and risk-model construction, and GSE26939 was used for external prognostic validation. The classification performance of the fixed signature for distinguishing primary LUAD from brain-metastatic LUAD samples was further evaluated in GSE161116 and GSE271259. Immune microenvironment features were assessed, and an LLM-assisted exploratory drug-screening strategy combined with molecular docking was used to prioritize candidate compounds. Results: Single-cell analysis suggested that metastatic epithelial cells exhibited enhanced anoikis-related activity, accompanied by macrophage-associated SPP1-CD44 and MIF-(CD74+CXCR4) communication patterns. Machine learning-based feature selection identified an eight-gene signature consisting of BIRC3, CCL20, CLEC7A, CTSL, GOLM1, ICAM3, MTUS1, and SERPINH1. The signature showed prognostic value in TCGA-LUAD and GSE26939 and demonstrated exploratory classification performance in distinguishing primary LUAD from brain-metastatic LUAD samples. High-risk patients exhibited immune microenvironment alterations and enrichment of tumor progression-related pathways. LLM-assisted compound prioritization and molecular docking highlighted resveratrol and SB431542 as hypothesis-generating candidates with predicted interactions with core targets. Conclusions: This study identified an anoikis-related eight-gene signature for LUAD prognostic stratification and exploratory brain metastasis-associated classification. The findings suggest the potential involvement of anoikis-related tumor–microenvironment interactions in LUAD brain metastasis and provide candidate genes and compounds for further experimental validation. Full article

Radiometabolic therapy is a mechanistically plausible but clinically underused strategy in lymphoma. Its rationale is based on the selective delivery of cytotoxic radiation to malignant lymphoid cells through antibodies, peptides, or small molecules directed against tumor-associated targets. Radioimmunotherapy with anti-CD20 agents, including 90Y-ibritumomab tiuxetan and 131I-tositumomab, demonstrated meaningful efficacy in B-cell non-Hodgkin lymphoma, particularly in indolent and relapsed/refractory settings. However, despite encouraging clinical results, its use progressively declined because of logistical, regulatory, commercial, and multidisciplinary barriers. More recently, renewed interest has emerged with the development of novel antibody–radionuclide conjugates and radioligand-based theranostic strategies targeting CD22, CD37, CD45, and CXCR4. Among these, CXCR4-directed imaging and therapy with 68Ga-pentixafor and 177Lu/90Y-pentixather illustrate image-guided patient selection and targeted radionuclide treatment in advanced hematologic malignancies. This narrative review summarizes evidence retrieved from Scopus and PubMed on radiometabolic therapy in lymphoma, with particular attention paid to established radioimmunotherapy, emerging targets, radioligand therapy, dosimetry, toxicity, and combination strategies with chemotherapy, immunotherapy, and hematopoietic stem cell transplantation. Available evidence supports the plausibility and possible clinical utility of these approaches, but remains heterogeneous and, for several newer targets, preliminary. Future development will require prospective trials, standardized imaging-based selection, individualized dosimetry, and integration within multidisciplinary lymphoma treatment pathways. Full article

Multiple sclerosis (MS) is a heterogeneous autoimmune disorder of the central nervous system of polygenic nature. Uncovering the genetic predictors of MS phenotype can help to explain the nature of the disease’s clinical heterogeneity, and contribute to the development of novel tools for precise disease prognosis. We conducted a retrospective genetic association study of 35 polymorphic variants in immune-related genes with MS severity assessed using the Multiple Sclerosis Severity Score (MSSS) in a sample of 548 Russian relapsing-onset MS patients who have not previously received immunomodulatory therapy. Variants in the CXCR5, EOMES, TNFRSF1A, IRF8, PVT1, CCR5, HLA-DRB1, IL6, TCF7, and CD40 genes were identified as MSSS-associated in at least two of the three models analyzed (MSSS > 3.5 versus ≤3.5; MSSS > 5.0 versus <2.5; MSSS as a continuous variable). Among them, variants in CCR5, HLA-DRB1 and IL6 genes were associated with MSSS only in women, while variants in the TCF7 and CD40 genes only in men. The variant in CXCR5 was MSSS-associated both in the total sample and in subgroups of female and male MS patients. Thus, we demonstrate that several GWAS-identified MS risk genes, along with other immunological loci, act as modifiers of the MS phenotype. Full article

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of ALL characterized by unfavorable clinical outcomes. Despite significant progress in deciphering the genetic and epigenetic landscapes of T-ALL, the underlying molecular mechanisms, particularly in non-early T-cell precursor (non-ETP) T-ALL, remain incompletely understood. In this study, functional assays were performed using three well-characterized non-ETP T-ALL cell lines. In vivo therapeutic efficacy was evaluated using non-ETP T-ALL xenograft models. Transcriptomic profiling was performed by RNA sequencing (RNA-seq) followed by bioinformatic analysis. Publicly available clinical datasets from T-ALL patients were mined to analyze survival outcomes. We found that activation of CD40 ligand (CD40LG) or CD28 accelerates cell-cycle progression and enhances the migratory capacity of non-ETP T-ALL cells, with CD40LG uniquely upregulating CXCR4 to mediate bone marrow tropism. Further RNA-seq and functional validation identified Rho GTPase signaling, specifically RhoA/Rac1/Rac2, as a pivotal downstream effector of CD40LG/CD28, leading to therapeutic resistance to PI3K inhibition. Pharmacological blocking RhoA or Rac1 using small-molecule compounds not only induces remarkable cytotoxicity but also sensitizes resistant cells to PI3K inhibitors, both in vitro and in vivo. Clinically, elevated expression of CD40LG, CD28, RHOA, or RAC2 correlates with poor prognosis in non-ETP T-ALL patients. These findings uncover a novel CD40LG/CD28-Rho GTPase axis as a key driver of pathogenesis and a potential therapeutic vulnerability in non-ETP T-ALL, providing a new target for precision intervention and a promising strategy to overcome therapeutic resistance. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) and the accumulation of tau in the brain, which triggers robust innate immune responses. Growing evidence indicates that neuroinflammation contributes to AD progression by overactivating microglia through the release of cytokines and chemokines. In general, chemokines can disrupt neuronal communication and promote blood–brain barrier permeability. Peripheral immune cells are mobilized into the brain by a gradient of chemokines. These processes link peripheral immune responses with substantial T-cell infiltration into the CNS parenchyma, leptomeninges and cerebrospinal fluid of both AD mice and AD patients. This finding underscores the relevance of the adaptive immune system, particularly T and B cells, in AD neuropathology. T-cell infiltration into the brain can influence amyloid clearance through chemokine signalling. However, chemokines play a critical role in AD by either promoting or suppressing disease progression. The infiltration of peripheral T and B cells into the brain parenchyma can exacerbate neuronal loss, yet it may also exert neuroprotective effects. Despite the presence of CD4⁺ and CD8⁺ T cells in postmortem brains of AD patients, debate continues about their role in AD brains, in terms of whether they are protective or detrimental. Understanding the complex role of chemokines in controlling innate and adaptive immune responses by modulating neuron–glia interactions (involving astrocytes and microglia) may provide novel therapeutic approaches for AD. Targeting chemokine signalling or treating with drugs that can prevent the recruitment of immune cells may be promising strategies for treating AD neuropathology. Therapies that prevent the overactivation of T cells in the brain could lead to protective strategies against AD. In fact, regulatory T cells (Tregs) could delay the onset of cognitive symptoms, because they suppress inflammation and slow the accumulation of Aβ plaques and p-Tau in the brain. Complementary strategies, such as photobiomodulation, nanoparticle, and T-cell-based approaches, could mitigate AD progression in patients. Full article

Background/Objective: Intracranial arteriovenous malformations (AVMs) are high-flow cerebrovascular lesions associated with a significant risk of intracranial hemorrhage, neurological morbidity, and mortality. Current management strategies, including microsurgical resection, endovascular embolization, stereotactic radiosurgery, and conservative observation, remain limited by procedural risk and uncertain long-term outcomes. Beta-blockers, particularly propranolol, have recently attracted interest as potential adjunctive therapies because of their vasoconstrictive, antiangiogenic, and vascular remodeling properties. This review evaluates the mechanistic rationale and current evidence regarding beta-blocker use in intracranial AVMs. Methods: A comprehensive literature review was conducted using PubMed, Scopus, and Google Scholar databases through January 2026 using combinations of the terms “arteriovenous malformation,” “AVM,” “beta-blocker,” “propranolol,” “angiogenesis,” “hemorrhage,” and “cerebral cavernous malformation.” Eligible studies included experimental investigations, translational studies, observational cohorts, case reports, clinical trials, systematic reviews, and meta-analyses evaluating beta-blocker use in intracranial AVMs or related vascular malformations. Studies unrelated to cerebrovascular lesions, duplicate reports, and non-English publications were excluded. Given the heterogeneity and limited volume of available AVM-specific literature, findings were synthesized narratively rather than through formal systematic review methodology. Discussion: Preclinical studies suggest that beta-blockers modulate molecular pathways implicated in AVM pathophysiology, including VEGF, HIF-1α, SDF1α/CXCR4, MMP-9, and Notch-associated signaling. These mechanisms may reduce abnormal angiogenesis, endothelial instability, and pathological vascular remodeling. Clinical evidence, however, remains limited to retrospective studies, perioperative reports, and indirect evidence from cerebral cavernous malformations. Observational studies have reported associations between beta-blocker exposure and certain favorable AVM characteristics, including lower rates of hemorrhagic presentation and less complex angioarchitecture. However, these findings are highly susceptible to confounding, reverse causation, and selection bias and should not be interpreted as evidence of disease modification. Conclusions: Beta-blockers cannot currently be recommended as definitive therapy for intracranial AVMs. Their established role remains perioperative hemodynamic control, while potential disease-modifying effects require validation through prospective studies and randomized clinical trials. Full article

Postherpetic neuralgia (PHN) is a chronic neuropathic pain condition that arises following varicella-zoster virus reactivation and represents a significant clinical burden. Despite known risk factors, the genetic basis of PHN remains poorly understood. This study aimed to identify genetic variants associated with PHN through the secondary analysis of GWAS summary data (GCST012124). One genome-wide significant locus (KIF1B) and several suggestive variants (PTPRZ1, PRKCE, CXCR4) were identified. These genes converge on pathways related to axonal transport, neuroinflammation, and nociceptive sensitization. Findings support a multifactorial genetic contribution to PHN and highlight potential targets for future research and therapeutic development. Full article

Waldenström macroglobulinemia is a rare lymphoplasmacytic malignancy characterized by bone marrow infiltration and monoclonal immunoglobulin M production. Despite its indolent clinical course, the disease exhibits considerable biological complexity driven by recurrent genetic alterations, dysregulated signaling pathways, and a supportive bone marrow microenvironment. The identification of MYD88 and CXCR4 mutations has significantly advanced understanding of disease pathogenesis, clonal evolution, and treatment response. Additional insights from cytogenetic, epigenetic, and microRNA studies have further refined the molecular landscape of this disorder. These advances have translated into improved therapeutic strategies, particularly with the introduction of Bruton’s tyrosine kinase inhibitors, although treatment resistance remains a clinical challenge. Other targeted approaches, including BCL2 and proteasome inhibition, offer additional options for personalized therapy. Ongoing integration of molecular and microenvironmental data is expected to enhance risk stratification and support the development of more effective, tailored treatment strategies. Full article

Primary sclerosing cholangitis (PSC) is a chronic inflammatory precursor associated with an increased risk of intrahepatic cholangiocarcinoma (ICC), yet identifying malignant features within the persistent inflammatory background remains challenging. In this study, a background-deviation framework was applied to explore malignant-associated determinants during PSC-associated cholangiocarcinogenesis. Single-cell RNA sequencing data from PSC, ICC tumor tissues, and adjacent non-tumor tissues were integrated, followed by functional enrichment, CellChat analysis, Monocle 2 pseudotime reconstruction, Non-negative Matrix Factorization (NMF), STRING/Cytoscape network analysis, and diagnostic signature construction using LASSO regression and exhaustive best subset selection. Single-cell profiling suggested disease-associated cellular remodeling, including cholangiocyte expansion in ICC samples. Functional and intercellular communication analyses indicated a putative transition from an immune-dominant PSC state toward a hyper-biosynthetic ICC-associated phenotype, accompanied by a possible MIF receptor-usage shift from CXCR4 to CD44. Monocle 2 and NMF further identified candidate malignant-associated trajectories and meta-programs, with MYC/TP63-related regulatory signals emerging as potential contributors. Based on these exploratory findings, best subset selection identified a two-gene transcriptomic candidate signature comprising PMAIP1 and GADD45A, which showed promising discriminative performance in internal cross-validation and an external tumor-versus-adjacent validation cohort. These findings provide a transcriptomic basis for further validation of PSC-associated cholangiocarcinogenesis and potential ICC surveillance markers. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) has a profoundly immunosuppressive tumour microenvironment (TME) that limits anti-tumour immunity and contributes to resistance to immunotherapy. Although γδ T-cells can integrate innate and adaptive immune signals, their abundance, transcriptional states and regulatory pathways in PDAC remain incompletely defined. Methods: We performed integrated single-cell RNA sequencing analysis of 39 pancreatic tissue samples, comprising 33 PDAC tumours and 6 adjacent normal tissues. After dataset integration, immune cell annotation, and stringent per-cell gating, γδ T-cells were quantified and profiled for checkpoint-, ligand-, and chemokine-related programmes. Results: γδ T-cells were detectable across PDAC samples but showed substantial inter-sample heterogeneity in abundance. Among candidate inhibitory pathways, PDCD1, CD274, and HAVCR2 expression in γδ T-cells did not differ significantly between tumour and adjacent tissues, whereas KLRC1 (encoding NKG2A) showed a tumour-associated difference at the single-cell level, with a consistent directional pattern in sample-level summaries. NKG2A expression was comparable between γδ T-cells and NK cells, suggesting a shared inhibitory programme. HLA-E, the ligand for NKG2A, showed higher epithelial-cell expression in tumour than adjacent tissue in sample-level summaries (median 1.06 vs. 0.57; BH-q = 0.035). Chemokine analysis identified enrichment of CCL2, CCL4, CCL5, CXCL8 and CXCL12, with limited CXCL9/10/11 signalling within the PDAC TME. Within γδ T-cells, CXCR4 was the trafficking receptor, followed by CCR6, CCR7 and CXCR6. Conclusions: PDAC-infiltrating γδ T-cells show marked inter-sample heterogeneity and variable inhibitory and trafficking-related programmes. Integrated transcriptomic analysis nominates HLA-E–NKG2A as a candidate regulatory axis, with NK cells included as a biologically relevant comparator. Chemokine receptor patterns, particularly CXCR4, CCR6, CCR7 and CXCR6, suggest candidate trafficking features. These findings are hypothesis-generating and require spatial, protein-level and functional validation. Full article

Chinese Simmental cattle are a high-quality breed developed through long-term crossbreeding and selection after their introduction into China and have become the main dual-purpose cattle population in the Xinjiang region. To deeply dissect the population structure, characteristics of the population structure, and the genetic basis of the twinning trait, this study focused on Xinjiang Chinese Simmental cattle as the main research subject. It integrated genomic data from global public databases to systematically conduct population structure analysis, genetic relationship analysis, and genome-wide selection signature analysis. Population genetic analysis revealed that the IBS matrix and G matrix indicated that some individuals from different geographical origins exhibited distant genetic relationships; the Xinjiang population showed the fastest LD decay, suggesting abundant genetic diversity; the inbreeding coefficient based on Runs of Homozygosity (ROH) across populations ranged from 0.036 to 0.063; principal component analysis and phylogenetic tree showed that some individuals from different geographical origins had certain genetic interconnections; admixture analysis indicated that K = 5 was the optimal model, with each population exhibiting clear genetic differentiation and admixture characteristics. Furthermore, by combining F_st and θπ analysis (comparing the Xinjiang population with other geographical populations), a total of 89 candidate genes associated with the twinning trait in Xinjiang Chinese Simmental cattle were screened, including CYP19A1, HORMAD1, GRB14, CADM2, CXCR4, and others that have been reported to be closely related to oogenesis and reproductive function. In summary, this study explores genome-wide genetic differences among Simmental cattle populations from different regions, deepens our understanding of their population structures, and offers new candidate genes and molecular markers for high-fecundity breeding in Simmental cattle. Full article

Viral comorbidities elicit complex host responses by activating redox-sensitive signaling pathways, prominently those regulated by NADPH oxidase (Nox) enzymes. Nox are critical components of host defense, generating reactive oxygen species (ROS) that modulate key cellular signaling cascades. Under normal physiological conditions, Nox activity is tightly controlled; however, viral infections frequently disrupt this regulation, leading to aberrant upregulation of specific Nox isoforms. Elevated expression of individual Nox enzymes has been observed in infections such as influenza A and hepatitis C virus, while simultaneous activation of multiple Nox isoforms occurs in HIV and SARS-CoV infections. Similar patterns of dual or multi-isoform Nox activation are also reported in complex disease states, including diabetes, thrombosis, and fibrosis. MicroRNAs play a crucial role in this process by selectively regulating Nox isoform expression during viral infection, thereby remodeling the host redox environment. Nox-derived ROS influence multiple downstream signaling pathways, including SMAD, MAPK, CXCR-mediated signaling, and the JNK/ERK axis, promoting inflammation and fibrosis that worsen viral disease outcomes. Additionally, several FDA-approved drugs, investigational agents, and microRNA-based therapeutics show promise in modulating Nox activity. Therefore, this article substantiates how viral infections reprogram host transcriptomic and redox signaling networks, contributing to viral pathogenesis and offering potential therapeutic intervention strategies. Full article

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal hematopoietic dysregulation, amplification of chronic inflammation, and progressive remodeling of the bone marrow fibrotic niche, clinically manifesting as bone marrow failure, splenomegaly, and systemic inflammatory symptoms. Although Janus kinase (JAK) inhibitors can alleviate symptom burden and reduce spleen size, they have limited capacity to eradicate malignant clones or reverse fibrosis. Allogeneic hematopoietic stem cell transplantation remains the only potentially curative option; however, its application is constrained by advanced age, comorbidities, unavailable donor, and transplant-related risks. Therefore, the development of disease-modifying therapeutic strategies has become a central focus in MF research. Chimeric antigen receptor T (CAR-T)-cell therapy has demonstrated robust efficacy across various hematologic malignancies. Its application in MF holds the potential not only to selectively eliminate malignant hematopoietic clones but also to modulate the immunosuppressive and profibrotic microenvironment through advanced cellular engineering, thereby enabling a dual therapeutic paradigm involving both clonal control and microenvironmental reprogramming. In this context, potential targets and pathways include CD123, myeloproliferative leukemia protein (MPL), fibroblast activation protein (FAP), the TGF-β signaling axis, the CXCR4–CXCL12 niche-regulatory axis, and molecules associated with myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Future strategies may optimize both efficacy and safety through combinatorial approaches, including integration with JAK inhibitors, development of armored CAR-T constructs, and bridging to hematopoietic stem cell transplantation. Collectively, CAR-T-cell therapy offers a promising avenue for shifting MF management from symptomatic control toward true disease modification. Full article

Colorectal cancer (CRC) remains a major global health burden and a leading cause of cancer-related morbidity and mortality. Current blood-based biomarkers lack sufficient sensitivity and specificity, particularly for early detection. In this context, circulating immune-cell transcriptomic profiling has emerged as a promising minimally invasive approach. This systematic review was conducted following a PROSPERO-registered protocol (CRD42024604757) and PRISMA 2020 guidelines to evaluate the diagnostic and prognostic potential of circulating monocyte-related transcriptomic profiles in CRC. Of 295 records identified, six studies met the inclusion criteria. The available evidence consistently supports the diagnostic value of circulating transcriptomic profiles in distinguishing patients with CRC from healthy individuals and in reflecting tumour-associated immune alterations. Monocyte-related signatures, including CXCR2⁺ monocytes, were associated with disease stage and metastatic features. Epitranscriptomic modifications, such as m6A and m5C, further reinforced their diagnostic relevance, with some studies reporting higher diagnostic accuracy than classical biomarkers. In contrast, evidence for prognostic value remains limited, heterogeneous, and often indirect, largely due to small sample sizes, methodological variability, and reliance on public datasets. Overall, circulating immune-cell transcriptomic profiles are promising non-invasive biomarkers for CRC detection and characterization, although their prognostic utility remains unclear. Methodological heterogeneity limits clinical applicability, highlighting the need for standardized, CRC-specific studies with cell-type-resolved approaches. Full article