Rituximab (RTX) is a first-line option for primary membranous nephropathy (pMN), but many patients fail to respond for reasons that conventional markers only partially explain. We assessed whether longitudinal peripheral immunophenotyping could identify cellular biomarkers of response. In a prospective single-center cohort of 35 patients with pMN treated with standard two-dose RTX, flow cytometry of B-cell, T-cell and monocyte compartments, the systemic inflammation response index (SIRI) and phospholipase A2 receptor antibody were assessed at baseline and months 3, 6 and 12. Within a mean of 7.48 ± 2.4 months, 23 patients (65.7%) achieved either partial or complete remission. By month three, responders showed deeper B-cell depletion, higher CD4+CD25+FoxP3+ T cells, fewer intermediate monocytes and a lower SIRI. On multivariate analysis, month-3 depletion of total CD3−CD19+ B cells below 0.5% (odds ratio 5.8, 95% confidence interval 1.1–31.1) was associated with remission, and each 0.1-unit increase in month-3 SIRI (odds ratio 0.44, 95% confidence interval 0.22–0.91) with lower odds of remission. In a hypothesis-generating analysis, a model combining both had an apparent area under the curve of 0.87. Longitudinal immunophenotyping identifies candidate biomarkers of RTX response in pMN that require multicenter validation.
Dietary interventions alter brain gene expression in diabetes, but the extent to which their responses agree across experiments and reduce differences from controls remains unclear. Five public transcriptomic datasets were reanalyzed, spanning human cortical fractions, rat brain regions, diabetic mouse hippocampus with intermittent fasting (IF), diabetic whole brain with ketogenic diet, and APP/PS1 and wild-type hippocampus with IF. Gene and pathway comparisons assessed agreement across experiments. Statistical tests distinguished opposing disease and dietary effects from reductions in the remaining distance from controls. IF and ketogenic diet identified 6569 and 999 genes, respectively, in diabetic mice. Their effects showed modest agreement (Pearson r = 0.205), with 447 genes significant in both experiments, including 359 with matching directions. They shared 59 pathways with a matching direction at a fixed intergene correlation of 0.01; these overlaps were not supported when correlations were estimated from the data. IF responses in diabetic and APP/PS1 hippocampus agreed poorly (r = −0.056). No human genes met a per-contrast false discovery rate < 0.05. Thirteen diabetic genes showed significant opposition of disease and IF effects; neither primary fasting experiment demonstrated contraction toward controls. The results support limited agreement between the diabetic dietary experiments and little agreement in IF responses across the examined disease contexts. They do not establish transcriptomic restoration.
DNA damage response (DDR) deficiencies are linked to tumorigenesis and progression. However, the association of DDR with prognosis and therapeutic response in glioma has not been fully illustrated. TCGA and CGGA databases were used to acquire RNA-seq and clinical data about gliomas. LASSO-Cox regression was introduced to establish a DDR-based risk signature. The single-sample gene set enrichment analysis (ssGSEA) algorithm was used to estimate immune infiltrates. The performance of the signature and nomogram in predicting survival was evaluated using ROC curves. Connectivity Map (CMap) analysis was used to nominate candidate compounds, and pRRophetic was used to predict drug sensitivity. Through LASSO-Cox regression, we developed a prognostic risk score based on five DDR-related genes (GADD45G, HDAC1, RRM2, SMC3, and WEE1). Higher risk scores were associated with shorter overall survival and remained significant in multivariable Cox analyses. A prognostic nomogram achieved 1-, 3-, and 5-year AUCs of 0.901, 0.936, and 0.903 in TCGA and 0.776, 0.816, and 0.802 in CGGA, respectively. High-risk tumors showed enrichment of TNFα signaling via NFκB and IL6/JAK/STAT3 gene sets, together with differences in inferred immune cell-associated features and immune checkpoint gene expression. Computational drug sensitivity analyses associated higher risk scores with lower predicted IC50 values for GSK269962A, pazopanib, rapamycin, and NVP-BEZ235, providing hypotheses for subsequent experimental validation. SMC3 overexpression inhibited glioma cell proliferation and migration in vitro. The DDR-related signature showed prognostic value and associations with immune-related transcriptional features in glioma, with in vitro evidence suggesting a functional role for SMC3.
The microbiota–gut–brain axis represents an important bidirectional communication network linking the gastrointestinal tract and the central nervous system and may contribute to processes involved in neurodegeneration. Increasing attention has been directed toward psychobiotics as potential modulators of the microbiota–gut–brain axis, while accumulating evidence also indicates that disturbed trace-element homeostasis may contribute to the pathogenesis of neurodegenerative diseases. This review summarizes current evidence on the roles of psychobiotics and trace elements and examines their potential interplay within the microbiota–gut–brain axis. The review discusses bidirectional interactions between the gut microbiota and trace elements, the potential effects of psychobiotic interventions on trace-element homeostasis, and the possible implications of these interactions for neurodegenerative processes. Taken together, current findings indicate that the gut microbiota, psychobiotics, and trace elements may constitute an interconnected system influencing intestinal and systemic homeostasis as well as biological processes relevant to nervous system function. However, direct evidence demonstrating the clinical relevance of interactions between these components remains limited. Moreover, available evidence is largely based on experimental studies, while clinical findings remain scarce and heterogeneous. Further characterization of this interplay may improve our understanding of mechanisms underlying neurodegeneration and provide a basis for the development of more targeted and personalized approaches to supporting neurological health.
Increased gastrointestinal iron absorption contributes substantially to iron overload in non-transfusion-dependent thalassemia (NTDT) patients. Resveratrol (RVT) and omeprazole (OMP) may reduce intestinal iron absorption and potentially complement iron chelation therapy. This randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of adjunctive RVT or OMP in adults with NTDT receiving stable iron chelation therapy. The primary outcome was the change in serum ferritin; secondary outcomes influenced serum iron (SI), transferrin saturation (TS), erythroferrone (ERFE), hepcidin, fetal hemoglobin (HbF), and safety. Participants with serum ferritin ≥ 300 ng/mL were randomized (1:1:1) to receive RVT 250 mg, OMP 20 mg, or the placebo (PLA) twice daily for 6 months. Thirty participants were randomized (RVT, n = 10; OMP, n = 11; PLA, n = 9), with a baseline median serum ferritin value of 629 ng/mL, interquartile range (IQR) 484–975. Serum ferritin decreased numerically over 6 months in the RVT and OMP groups relative to PLA; however, no significant treatment × time interactions or adjusted between-group differences in changes from the baseline were observed. Although significant within-group changes were observed for selected iron-regulatory biomarkers, including hepcidin, ERFE, and TS, these were not accompanied by significant treatment × time interactions and did not demonstrate differential treatment effects. Both interventions were generally well tolerated, and no serious adverse events were reported. In this underpowered trial, neither adjunctive RVT nor OMP demonstrated statistically significant treatment-specific effects on serum ferritin or other iron-related outcomes when compared with the placebo. The observed numerical trends warrant evaluation in larger, adequately powered trials. Trial Registration: ISRCTN73258526.
