Background: In non-small-cell lung cancer (NSCLC), high metabolic gene expression during immunotherapy can reflect either more infiltrating cells or altered cellular activity. We tested whether separating cell abundance from cell-intrinsic transcription clarifies incomplete tumour clearance after neoadjuvant programmed cell death-1 (PD-1) blockade.
Methods: Using cross-dataset triangulation, we analysed 1173,843 post-treatment immune cells from 224 patients (103 non-major pathological response [non-MPR], 40 major response, and 81 complete response) via patient-level regressions adjusted for clinical covariates, cell proportions, and library size. Findings were compared across recurrence follow-up (n = 154), spatial profiling (n = 40), three bulk cohorts (n = 78), population data (n = 3045), and 7224 genetic tests.
Results: Non-MPR tumours had higher regulatory T-cell (Treg) proportions (+3.91% FOXP3+, +3.07% CCR8+) and elevated lymphoid glycolysis, exhaustion, Treg, and adenosine scores (all false-discovery rate q ≤ 1.09 × 10-7). Notably, adjusting for cell composition and depth abolished broad glycolysis and exhaustion differences, whereas adenosine-associated transcription persisted (difference 0.044, 95% confidence interval [CI] 0.020-0.068; q = 0.0046), peaking in terminally exhausted CD8+ T cells (0.449, 95% CI 0.328-0.571; q = 1.29 × 10-10). Paired spatial biopsies localized HK2, LDHB, and SLC16A1 to tumour regions (q ≤ 0.0057) and CTLA4 to stroma (q = 5.14 × 10-5) without response interactions. A six-component score discriminated non-MPR (apparent area under the curve [AUC] 0.791, 95% CI 0.724-0.851) and recurrence (hazard ratio 1.41, 95% CI 1.04-1.93), attenuating after pathology adjustment, but failed in pre-treatment bulk cohorts (AUCs 0.091-0.517); no genetic test passed correction (q ≥ 0.9934).
Conclusions: Incomplete response involves Treg accumulation and cell-intrinsic adenosine transcription, offering exploratory, hypothesis-generating insights for prospective validation.
In oncology, glioblastoma multiforme (GBM) is considered a crucial challenge due to rapid drug resistance and the protective effects of the blood-brain barrier (BBB). Photodynamic therapy (PDT), photothermal therapy (PTT), and sonodynamic therapy (SDT) have emerged as promising approaches for GBM treatment, while limited energy penetration through the skull can restrict their effectiveness in intracranial tumors. The present systematic review aimed to evaluate studies on nanoparticle-based PDT, PTT, and SDT using online databases, including PubMed, Scopus, Web of Science, and Embase, from 2020 to 2025. Non-English studies, reviews, abstracts, book chapters, and retracted papers were excluded. A total of 663 records were initially identified, and 47 studies met the inclusion criteria. Based on the analysis of these studies, we observed a progressive shift in therapeutic strategies, categorized into four generations: (1) surface-limited ablation using near-infrared (NIR)-I thermal cytotoxicity; (2) multimodal synergistic therapies; (3) stimuli-responsive switch-on systems; and (4) deep-penetration modalities. The fourth generation is characterized by technologies, such as NIR-II lasers, X-ray-induced photodynamic therapy (X-PDT), low-intensity ultrasound (LIUS) and focused ultrasound, to overcome the depth barrier and promote immunogenic cell death. Nanoparticle-based GBM therapies are increasingly shifting toward multifunctional, BBB-targeted, and immune-engaging platforms. This trend highlights the need for multimodal, standardized, safe, and simpler designs.
Lung cancer mortality is driven largely by metastasis, which arises from tumor-intrinsic alterations and interactions within the tumor microenvironment (TME). Non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, circRNAs, and extracellular vesicle-associated RNAs, regulate these interactions by modulating gene expression and intercellular signaling. This review examines ncRNA-mediated regulation of metastatic signaling in lung cancer, with particular emphasis on TGF-β signaling and its crosstalk with five additional pathways relevant to tumor dissemination: Wnt/β-catenin, hypoxia-inducible factor signaling, Notch, integrin/focal-adhesion signaling, and the CXCL12/CXCR4 axis. Particular attention is given to epithelial-mesenchymal transition, cancer stemness, extracellular matrix remodeling, angiogenesis, immune escape, and metastatic niche formation. The available evidence indicates that ncRNAs often act through interconnected regulatory circuits rather than isolated targets, and that their effects depend strongly on histological context, including LUAD, LUSC, other NSCLC subtypes, and SCLC, as well as on molecular background, cellular compartment, and experimental model. Findings derived from one histological or molecular setting should therefore not be assumed to apply uniformly across lung cancer. Hypoxia, cancer-associated fibroblasts, tumor-associated macrophages, and extracellular vesicles can alter ncRNA programs, while ncRNAs can reciprocally reshape these components. We also examine the potential translational relevance of ncRNA-based biomarkers and therapeutic strategies; however, most remain at the preclinical or exploratory stage and require further mechanistic, analytical, prospective, and clinical validation. Major barriers include delivery, target specificity, extracellular-vesicle standardization, reproducibility, and patient selection. A network-based interpretation may therefore provide a more realistic framework for understanding ncRNA contributions to lung cancer metastasis.
Background: Oxidative stress and redox dysregulation are important features of hepatocellular carcinoma (HCC), but their expression patterns in hepatitis B virus (HBV)- and hepatitis C virus (HCV)-associated HCC remain incompletely characterized. This study investigated redox-related gene expression and its potential functional and prognostic relevance.
Methods: A predefined 84-gene oxidative stress and redox-related quantitative real-time PCR array was used to profile 11 HCC samples (7 HCV-associated and 4 HBV-associated tumors) and 4 controls. Analyses included hierarchical clustering, gene-list overlap, functional enrichment, protein-protein interaction networks, gene-expression correlations, and exploratory survival analysis.
Results: Both HCC groups exhibited altered expression of genes associated with antioxidant defense, glutathione metabolism, mitochondrial redox regulation, and ferroptosis-related processes. In HCV-associated HCC versus controls, TXN, SPINK1, HSP90AA1, and DUSP1 showed increased expression. In HBV-associated HCC versus controls, GCLC, peroxiredoxins, CAT, and SOD1 showed increased expression. Eighteen genes were shared between comparison lists, including GPX4, GPX2, GPX3, PRDX1, PRDX5, TXN, GCLM, SOD2, and FTH1. Enrichment analyses implicated glutathione metabolism, oxidative stress, peroxisome function, and ferroptosis-associated processes. Network analysis identified GPX2, GPX3, GPX4, and SOD2 in a connected module. External exploratory survival analysis associated higher SPINK1 and HSP90AA1 expression with poorer overall survival.
Conclusions: These findings identify redox-related expression patterns warranting further investigation. Larger cohorts and functional studies are needed to establish etiological differences, ferroptosis susceptibility, and prognostic significance.
Background: Colposcopy-directed biopsy is widely used in the diagnosis of cervical dysplasia, but its accuracy is variable. Reliable detection of clinically significant lesions (CIN2+) is essential for appropriate treatment. This study assessed its diagnostic performance using histology after LEEP as the reference standard and explored factors associated with discrepancies.
Methods: 423 procedures were analyzed. Histological findings from colposcopy-directed biopsy were compared with the histology of the subsequent LEEP specimen. Diagnostic performance for CIN2+ was evaluated using sensitivity, specificity, predictive values, and accuracy; agreement was assessed using weighted Cohen's kappa. Subgroup analyses considered transformation zone (TZ) type, age, and menopausal status. Multivariable logistic regression assessed predictors of histopathological underestimation.
Results: Biopsy showed 97.0% sensitivity, 20.0% specificity, and 80.6% accuracy for CIN2+ detection. Exact histological agreement occured in 61.7% of procedures (κ = 0.31). Histopathological underestimation occurred in 12.3% and overestimation in 26.0%, indicating a tendency toward overestimation. Exact agreement decreased from 75.8% in TZ1 to 48.0% in TZ3 and from 65.2% in premenopausal to 48.4% in postmenopausal patients. Complete-case multivariable analysis included 227 procedures and 23 underestimation events. Compared with TZ1, TZ2 and TZ3 were independently associated with higher odds of underestimation other included covariates were not.
Conclusion: Colposcopy-directed biopsy shows high sensitivity but limited specificity for CIN2+ detection, with notable diagnostic discrepancies. Histological concordance was lower in patients with TZ 3 and in postmenopausal women, while TZ was independently associated with underestimation. These findings highlight the importance of considering anatomical and patient-related factors when interpreting biopsy results and planning clinical management.
Introduction: The gut microbiota may influence breast cancer risk through different biologic pathways. This analysis examined the association of the gut microbial composition with percent mammographic density (PMD), a strong predictor of breast cancer risk.
Methods: Postmenopausal women in the Adiposity Phenotype Study, a cross-sectional subset of the Multiethnic Cohort, from five racial/ethnic groups, provided a stool sample. Extracted bacterial DNA was sequenced for the V1-V3 region of the 16S rRNA gene. Bioinformatic analysis determined alpha-diversity and the abundance of 10 phyla and 152 genera. PMD was assessed in routine mammograms taken before stool collection with a quantitative computer-assisted method. Blood levels of estrogen metabolites were assessed using standard assays. General linear models regressed PMD on gut microbial diversity, phyla, and genera while adjusting for relevant covariates.
Results: Of 649 women (69.1 ± 2.7 years), 311 had low (<15%) and 338 had high (>=15%) PMD. Whereas alpha diversity or phyla were not associated with PMD, 10 genera were nominally related to PMD (p < 0.05) but not after adjusting for multiple comparisons: 7 positively (Bifidobacterium, Blautia, Dialister, Eubacterium_fissicatena_group, Lachnospira, Lachnospiraceae_UCG-008, Lachnospiraceae_uncultured) and 3 inversely (Alistipes, Senegalimassilia, Eubacterium_oxidoreducens_group), potentially implicating estrogen metabolism and short-chain fatty acid production. All blood steroid metabolites were significantly related to PMD, but only SHBG was associated with 2 genera after Bonferroni adjustment.
Conclusions: The nominal associations detected in this analysis suggest that certain gut microbiota may be associated with PMD, a marker of risk but not a measure of breast cancer incidence, due to their ability to affect circulating hormones or SCFA production.
Objectives: This study aims to evaluate the therapeutic efficacy and safety of tumor vaccine therapy in patients suffering from Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL).
Methods: a systematic search was done in PUBMED, WOS, Embase and Scopus in order to identify relevant studies from their inception to February 8th, 2026. At first, title and abstract of retrieved records were checked for eligibility and then, a full-text evaluations were conducted. Then relevant data were extracted from eligible studies. Risk of Bias of Included studies were assessed using Cochrane ROB-2 and ROBINS-I tool. Proportions were estimated using the metaprop function of the R meta package with logit transformation and back-transformation for presentation. Because of substantial clinical and methodological heterogeneity, results were not pooled; instead, individual study estimates with 95% confidence intervals were presented in forest plots for qualitative comparison.
Results: Across studies of non-Hodgkin lymphoma, objective response rates varied from 6% to 44%, with complete response rates ranging from 0% to 28% and partial response rates from 6% to 29%. Response estimates varied across treatment-naïve, relapsed/refractory, and mixed-treatment populations, without a consistent pattern according to previous treatment status; most studies evaluated patients with active disease and predominantly indolent NHL. Grade 3-5 adverse events ranged from 0% to 19%, with no severe events reported in most studies, although treatment strategies and concomitant therapies differed substantially across cohorts. Only one study evaluated Hodgkin lymphoma, reporting an ORR of 66.7% (2/3), consisting entirely of partial responses, with no grade 3-5 adverse events. Given the marked clinical and methodological heterogeneity, findings were synthesized descriptively without pooled effect estimates.
Conclusion: Therapeutic tumor vaccines showed variable but measurable antitumor activity in NHL, with generally low rates of grade 3-5 adverse events across most studies. However, substantial clinical and methodological heterogeneity, small sample sizes, non-randomized designs, and highly limited evidence in HL prevent firm conclusions regarding efficacy or comparative effectiveness. Stronger comparative evidence from multicenter cohorts and registries with longitudinal follow-up, appropriate control groups, and propensity-score methods is needed to clarify vaccine-associated clinical responses and identify settings suitable for subsequent randomized evaluation.
Background: Fruquintinib is a standard later-line treatment for advanced colorectal cancer (aCRC) after oxaliplatin- and irinotecan-based chemotherapy. Prospective studies of fruquintinib-based programmed cell death protein-1 (PD-1) inhibitor strategies in aCRC reported as mismatch repair-proficient (pMMR) or microsatellite-stable (MSS) have yielded heterogeneous outcomes. We summarized observed survival and response outcomes using reconstructed individual-level records.
Methods: PubMed, Embase, Web of Science, and CENTRAL were searched from inception through January 26, 2026. Published Kaplan-Meier curves were digitized and converted to reconstructed individual-level time-to-event records with IPDfromKM in R. Merged Kaplan-Meier curves were treated as patient-weighted descriptive composites. Objective response rate (ORR) and disease control rate (DCR) were synthesized with random-effects models. Sensitivity analyzes excluded the prospective observational study and restricted the evidence to pharmacologic fruquintinib plus PD-1 doublets.
Results: Five prospective studies enrolled 150 patients; 147 contributed to reconstructed overall survival (OS) and progression-free survival (PFS) analyzes. Median OS and PFS were 11.7 and 5.4 months, respectively. Reconstructed duration of response included 14 responders from three studies and had a median of 8.8 months. In the aggregate response dataset (149 observations), ORR was 19% and DCR was 82%. In the doublet-only sensitivity analysis, median OS and PFS were 14.8 and 6.9 months, respectively.
Conclusion: These results descriptively summarize small, heterogeneous, uncontrolled studies and do not estimate a common treatment effect or the added benefit of PD-1 blockade. The overall composite should not be used as a uniform doublet benchmark or as the sole basis for clinical decisions or trial sizing.
PIWI-interacting RNAs (piRNAs) and their associated proteins constitute an important regulatory system involved in genome stability, transposable-element repression, germ-cell development, and epigenetic regulation. Increasing evidence indicates that disruption of piRNA-associated proteins contributes to reproductive disorders and tumorigenesis through alterations in DNA methylation, histone modifications, RNA stability, and transposable-element activity. This review summarizes current evidence on the epigenetic functions of piRNA-associated proteins in infertility and cancer, with particular emphasis on TDRKH, PNLDC1, TDRD9, HENMT1, MORC1, MORC3, and other components of the piRNA pathway. Studies in mouse and zebrafish models demonstrate that defects in these proteins can impair piRNA biogenesis or stability, disrupt transposon silencing, alter germ-cell development, and result in male or female infertility. In human and cancer models, dysregulation of piRNA pathway components has been associated with ovarian, cervical, esophageal, breast, leukemia, and prostate cancers, with evidence implicating DNA and histone methylation as well as RNA modifications such as m6A and m5C. Collectively, these findings suggest that piRNA-associated proteins can act as important epigenetic regulators linking small-RNA-mediated mechanisms to genome integrity, reproductive function, and malignant transformation. Further characterization of these pathways may improve understanding of disease mechanisms and support the identification of potential diagnostic and therapeutic targets.
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