Search Results (9,604)

Pain is a complex process involving dynamic transcriptional changes in cells of the PNS and CNS following injury or inflammation. Among stress-inducible transcription factors, ATF3 has emerged as one of the most robust molecular markers of neuronal injury, particularly in sensory neurons of the DRG. Although ATF3 is widely used as an indicator of axonal damage in experimental pain models, its functional contribution to the initiation, maintenance, and resolution of pain remains poorly understood. Recent transcriptomic and functional studies suggest that ATF3 not only reflects neuronal stress but also orchestrates gene expression programs involved in axonal regeneration, neuroimmune communication, ion channel remodeling, and nociceptor plasticity. Moreover, ATF3 expression has been identified in non-neuronal cell populations, including Schwann cells and satellite glial cells, indicating broader roles in peripheral nerve repair and neuroinflammation. Despite the growing body of experimental evidence, the literature remains fragmented, and no consensus has yet been reached as to whether ATF3 primarily promotes adaptive regeneration or directly contributes to maladaptive pain signaling. This review aims to provide a comprehensive and critical overview of the current understanding of ATF3 biology in pain, building on evidence from transcriptomic and molecular analyses, experimental models of neuropathic, inflammatory, and cancer-associated pain, and emerging mechanistic insights into its role in pain-related neuronal plasticity. This review examines the regulation of ATF3 expression, its downstream transcriptional targets, its interactions with inflammatory signaling pathways, and its potential value as a therapeutic target. By consolidating current evidence and highlighting existing knowledge gaps, this review seeks to clarify the multifaceted role of ATF3 in pain pathophysiology. Full article

Background/Objectives: Rare cervical tumors account for about 10–15% of cervical cancers and are often misclassified at first diagnosis. Their recognition depends on subtype-directed immunohistochemistry, which excludes metastatic mimics, and on high-risk HPV (hrHPV) testing, which establishes HPV status. Published series rarely report how the diagnosis was reached. We therefore documented the full diagnostic work-up, together with treatment and outcomes, in a consecutive single-center series. Methods: This was a retrospective, single-center case series (January 2020–January 2025). Rare tumors were defined per the 2020 WHO Classification as subtypes other than squamous cell carcinoma and usual-type adenocarcinoma. Immunohistochemistry was used to confirm lineage and exclude mimics. hrHPV DNA testing and p16 immunohistochemistry were performed where tissue permitted. A tumor was called HPV-associated only when block-positive p16 accompanied hrHPV DNA; HPV DNA alone was not accepted as evidence of an HPV-driven tumor. Results: Ten patients were included (median age of 53 years). There were two signet-ring cell adenocarcinomas, two small cell neuroendocrine carcinomas (SCNECC), two serous adenocarcinomas, and one each of sarcomatoid carcinoma, clear cell carcinoma, granulocytic sarcoma, and poorly differentiated adenosquamous (glassy cell) carcinoma. hrHPV DNA was detected in six of the seven tumors tested. Three of these six were p16-negative: one serous, the clear cell, and the glassy cell carcinoma. Because block-positive p16 is the validated marker of transcriptionally active hrHPV, we classified these three as HPV-independent. This matches the known biology of these histotypes. Lymphovascular space invasion was present in eight patients (80%). Over a median follow-up of 10.5 months, four patients developed distant metastases, and three died. Conclusions: Accurate diagnosis of rare cervical tumors requires subtype-directed immunohistochemistry to exclude mimics and hrHPV testing interpreted together with p16; HPV DNA positivity alone does not establish HPV association. Given the small, heterogeneous series, outcome data are descriptive and hypothesis-generating. We propose a diagnostic algorithm and immunohistochemical framework and advocate centralized review and prospective registries. Full article

Despite advances in systemic therapy, many early breast cancer patients experience recurrence due to subclinical minimal residual disease (MRD). Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) have emerged as promising liquid biopsy markers for post-treatment MRD detection. This pre-registered systematic review and meta-analysis (PROSPERO/PRISMA 2020) evaluated their comparative prognostic significance. Seven databases were searched from inception to March 2026. Eligible studies included early breast cancer patients undergoing post-treatment ctDNA or CTC assessment after neoadjuvant or adjuvant therapy, reporting survival outcomes with extractable hazard ratios. Quality was assessed using the QUIPS tool; random-effects meta-analyses used the REML estimator. Seventeen studies (thirteen ctDNA, four CTCs; n = 3030) were included. Post-treatment CTC positivity was significantly associated with poorer survival (pooled HR = 2.99, 95% CI: 1.99–4.49; I² = 17.2%). ctDNA positivity demonstrated a substantially stronger prognostic effect (pooled HR = 10.28, 95% CI: 6.32–16.70; I² = 47.3%). Subgroup analyses identified assessment timing as a key heterogeneity source, with stronger effects after adjuvant (HR = 20.62; k = 4) versus neoadjuvant therapy (HR = 6.07; k = 9); given the small number of post-adjuvant studies, this finding is hypothesis-generating. No significant publication bias was detected. Both markers were significant prognostic markers of MRD. ctDNA showed a stronger pooled prognostic association, although no study assessed both biomarkers within the same cohort and direct head-to-head comparisons therefore remain lacking. Prospective randomized trials are needed to evaluate MRD-guided treatment strategies. Full article

Gastric cancer remains a major cause of cancer mortality worldwide, mainly due to its frequent diagnosis at advanced stages and the high probability of recurrence even after curative treatment. Conventional postoperative follow-up is mainly based on imaging studies, endoscopy and serological tumor markers, such as carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 72-4 (CA72-4)This narrative review was based on a structured literature search of PubMed, Scopus, Web of Science, MEDLINE, the Cochrane Library, and ClinicalTrials.gov from database inception through June 2026, with 75 studies included in the final narrative synthesis. Among these analytes, circulating tumor DNA (ctDNA)currently provides the most mature data for the detection of molecular residual disease and postoperative risk stratification. Although it allows for the early detection of recurrent or residual disease prior to imaging confirmation, postoperative ctDNA has shown significant prognostic value in many studies; however, routine use as a basis for decision-making in treatment planning is still considered investigational and will require future prospective clinical validation. Tumor-informed ctDNA approaches offer high analytical specificity and sensitivity in low-burden disease settings. In contrast, tumor-agnostic approaches, such as methylation analysis and fragmentomics, may improve the scalability of the method. However, they require further validation in the postoperative setting. At the same time, emerging data indicate that extracellular vesicles, exosomal RNA and peritoneal lavage analytes can provide complementary biological information, especially in cases of peritoneal dissemination. Despite the significant prospects, the use of liquid biopsy in guiding the treatment of gastric cancer remains under investigation. This is because even today there are limitations. Characteristic are the low ctDNA excretion and the anatomical heterogeneity of the disease, as well as clonal hematopoiesis. Limitations also include the lack of standardization as well as the cost and the need for prospective clinical studies. This review summarizes the biological basis of molecular residual disease, liquid biopsy technologies, ctDNA data, the concept of molecular recurrence, and the future prospects of multi-analytic and artificial intelligence (AI)-assisted surveillance models in gastric cancer. Full article

Background: Gastric cancer is often diagnosed in advanced stages for patients in countries without organized screening processes. Non-invasive biomarkers have been proposed to risk-stratify and identify those who should undergo endoscopy. Methods: We searched PubMed/MEDLINE, Scopus, and Google Scholar for studies published between January 2006 and May 2026 reporting diagnostic accuracy or health–economic outcomes for gastric cancer detection in asymptomatic adults or patients with precursor mucosal lesions. Twenty-five studies met eligibility criteria and were synthesized narratively, with reporting informed by PRISMA-DTA and Ferrari guidance. Results: Systemic inflammatory indices derived from routine blood counts are inexpensive but non-specific, with individual areas under the receiver operating characteristic curve (AUC) between 0.65 and 0.83. Serological markers of mucosal atrophy have a clearer biological basis and carry the review’s only large Western validation dataset but preferentially detect corpus-predominant disease. Liquid biopsy platforms report the highest accuracy, up to an AUC of 0.968, though sensitivity falls to 62.4% for precancerous lesions and to 44% for stage I disease on some platforms. Magnifying narrow-band imaging reported the highest accuracy among the endoscopic modalities reviewed, with an AUC of 0.97. In low-incidence Western settings, one-time serum pepsinogen screening with endoscopy reserved for positive results is cost-effective at USD 4913 per QALY gained. Conclusions: Reported accuracy is encouraging across all four classes of gastric cancer markers but derives mainly from retrospective East Asian case–control cohorts and declines at the earliest stages of disease. The evidence supports using these markers to triage toward endoscopy rather than to diagnose directly. Validation in Western populations remains a gap. Full article

Background/Objectives: Ubiquitin C-terminal hydrolase L1 (UCHL1) exhibits context-dependent roles in various cancers, but its clinical significance and biological functions specifically in colorectal cancer (CRC) remain incompletely understood. Methods: We systematically evaluated UCHL1 expression, clinicopathological associations, prognostic value, and immunological role in CRC using multiple public databases (TCGA, GTEx, UALCAN, GEPIA2, GSCA, and ENCORI) combined with immunohistochemical validation on a tissue microarray containing 80 paired CRC and adjacent normal tissues. Functional enrichment was assessed using ssGSEA, and immune cell infiltration was analyzed using the immunedeconv R package. The immunotherapy response was evaluated using the TIDE algorithm. Results: UCHL1 mRNA and protein levels were significantly downregulated in CRC tissues compared with normal tissues. Paradoxically, high UCHL1 expression was significantly associated with advanced T stage, N stage, TNM stage, and poor overall and disease-free survival. ssGSEA revealed positive associations with multiple aspects of oncogenic pathways, including tumor inflammation signature, tumor proliferation signature, epithelial–mesenchymal transition markers, extracellular matrix-related genes, angiogenesis, apoptosis, and G2M checkpoint regulation. Notably, UCHL1 expression was positively correlated with computationally estimated infiltration of macrophages, CD4⁺ T cells, and CD8⁺ T cells, and with elevated expression of immune checkpoint genes, as well as higher TIDE scores. These correlative findings suggest a potential association with immunotherapy-related pathways that warrants further investigation. Conclusions: UCHL1 is downregulated in CRC, but its elevated expression is associated with aggressive disease and poor prognosis. It is implicated in multiple oncogenic pathways and may contribute to an immunosuppressive tumor microenvironment, suggesting its potential as a candidate prognostic biomarker that warrants further functional investigation. Full article

Background and Objectives: Oxidative stress and chronic inflammation are closely interconnected processes involved in colorectal cancer (CRC) development and progression. However, the relationships between oxidative stress biomarkers, emerging hematological inflammatory indices, clinicopathological characteristics, and survival outcomes remain insufficiently characterized. This study evaluated circulating levels of 8-epi-prostaglandin F2α (8-epi-PGF2α), malondialdehyde (MDA), and superoxide dismutase 1 (SOD1), together with conventional and novel inflammatory indices, including the mean corpuscular volume-to-lymphocyte ratio (MCVL) and cumulative inflammatory index (IIC), in patients with CRC. Materials and Methods: This prospective observational study included 140 patients with histologically confirmed CRC and 40 healthy controls. Serum concentrations of 8-epi-PGF2α, MDA, and SOD1 were measured by ELISA, and hematological inflammatory indices were calculated from complete blood counts. Associations with clinicopathological characteristics were evaluated using non-parametric analyses with correction for multiple testing where appropriate. Spearman correlations with false discovery rate correction were used to assess oxidative–inflammatory associations. Prognostic analyses included 24-month time-dependent receiver operating characteristic (ROC) analysis accounting for censoring, Kaplan–Meier analysis, and Cox proportional hazards regression for overall survival (OS) and progression-free survival (PFS). Results: CRC patients exhibited significantly higher serum levels of 8-epi-PGF2α (p = 0.016), MDA (p < 0.001), and SOD1 (p < 0.001) than controls. Oxidative stress biomarkers differed significantly across TNM stage, nodal status, and histological grade, although the observed patterns were not uniformly progressive with disease stage. After false discovery rate correction, MDA retained significant correlations with multiple hematological inflammatory parameters, whereas SOD1 showed a more restricted correlation profile and 8-epi-PGF2α showed no significant correlations. At 24 months, MDA demonstrated the highest time-dependent discrimination for OS (AUC = 0.920; bootstrap 95% CI: 0.834–0.978), whereas its discrimination for PFS was modest (AUC = 0.636; bootstrap 95% CI: 0.487–0.773). High MDA, defined by the internally derived 24-month threshold, was associated with shorter PFS after adjustment for age, sex, and TNM stage (HR = 2.49, 95% CI: 1.29–4.80; p = 0.006) and, separately, metastatic status (HR = 2.40, 95% CI: 1.22–4.72; p = 0.011). However, when modeled continuously, MDA was no longer significantly associated with PFS after multivariable adjustment. Conclusions: CRC was associated with increased circulating oxidative stress biomarkers, with MDA showing the most consistent relationships with systemic inflammatory parameters and survival outcomes. Its prognostic association with PFS was dependent on the modeling approach, while its high discrimination for 24-month OS should be interpreted cautiously because of the limited number and metastatic restriction of death events. These findings identify MDA as a promising candidate oxidative–inflammatory marker warranting external validation rather than an independently established prognostic biomarker. Full article

Background: Lung cancer remains the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Over the past decade, immune checkpoint inhibitors have become a core component of first-line treatment for advanced-stage NSCLC lacking driver mutations. Programmed death-ligand 1 (PD-L1) expression is currently used as the standard biomarker, yet its predictive value remains limited, and in most immunotherapy trials, treatment efficacy has been observed independently of PD-L1 expression status. Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator, promotes immune escape by suppressing antigen presentation and impairing CD8+ T-cell function, thereby generating an immune-cold tumor microenvironment, positioning it as a promising candidate biomarker. Methods: We retrospectively analyzed 102 NSCLC patients treated with immunotherapy at a single center between 2018 and 2024. EZH2 expression was assessed by immunohistochemistry. A cohort-derived 25% threshold was used for the primary exploratory analysis, and the analyses were repeated using a 50% threshold as a sensitivity analysis. Patients were classified as EZH2-high (45.1%) and EZH2-low (54.9%) at the 25% threshold. Results: At the 25% threshold, objective response rate (ORR) was 53.6% in the EZH2-low group and 45.7% in the EZH2-high group (Fisher’s exact p = 0.551), while disease control rate (DCR) was 64.3% and 60.9%, respectively (p = 0.837). Median overall survival (OS) was 37 versus 27 months (log-rank p = 0.323), and median progression-free survival (PFS) was 15 versus 12 months (p = 0.387). No significant correlation was found between EZH2 and PD-L1 expression (r = 0.167, p = 0.138). In treatment-line-adjusted Cox models, EZH2 expression was not associated with OS (hazard ratio (HR) 0.953, 95% confidence interval (CI) 0.533–1.704; p = 0.870) or PFS (HR 0.996, 95% CI 0.573–1.733; p = 0.989), whereas squamous histology was an independent predictor of survival. Results remained non-significant at the 50% threshold. Early progression was uncommon and did not differ significantly by EZH2 status overall or within PD-L1 strata. Conclusions: In this real-world cohort, EZH2 expression was not independently associated with response, early progression, OS, or PFS, and showed no correlation with PD-L1. These exploratory findings do not support the clinical use of EZH2 as a biomarker at this stage; prospective, multicenter studies using predefined thresholds and standardized immunohistochemical methods are needed to clarify its potential role as a marker complementary to PD-L1. Full article

Background: Early detection of hepatocellular carcinoma (HCC) is critical for improving patient outcomes; however, ultrasound-based surveillance has limited sensitivity and variable performance across patient populations. We evaluated the performance of a multitarget HCC blood test (mt-HBT), incorporating methylated DNA markers, alpha-fetoprotein (AFP), and patient sex, across clinically relevant subgroups. Methods: We performed a subgroup analysis of a multicenter, prospective case-control study that included 159 patients with early-stage HCC (Barcelona Clinic Liver Cancer Stage 0/A) and 649 control patients with cirrhosis or chronic hepatitis B without HCC. The mt-HBT combined methylated HOXA1, TSPYL5, and B3GALT6 markers with AFP and sex. Sensitivity and specificity were evaluated overall and according to age, sex, obesity, liver disease etiology, Child Pugh class, and tumor size. Performance was compared with AFP and GALAD. Results: Overall sensitivity and specificity of mt-HBT for early-stage HCC detection were 76.7% (95% CI, 69.6–82.6) and 87.5% (95% CI, 84.8–89.8), respectively. Sensitivity was significantly higher than that of AFP (35.2%, p < 0.001) and comparable to that of GALAD (78.6%, p = 0.56), whereas specificity was lower than that of AFP (98.5%, p < 0.001) but higher than that of GALAD (76.9%, p < 0.001). Sensitivity was maintained across key subgroups, including patients with obesity (68.9%), Child Pugh B cirrhosis (75.0%), hepatitis C (80.0%), hepatitis B (72.2%), alcohol-associated liver disease (80.5%), and metabolic dysfunction-associated steatotic disease (69.0%) (all p > 0.05 between subgroups). Specificity exceeded 80% in all examined populations and was significantly higher in women than in men (92.5% vs. 83.9%, p < 0.001). Sensitivity increased with tumor size, ranging from 60.0% for tumors < 2 cm to 100% for tumors > 5 cm. Conclusions: The mt-HBT demonstrated robust, consistent performance for early-stage HCC detection across diverse patient populations, including subgroups in which ultrasound surveillance commonly underperforms. These findings support the prospective validation of mt-HBT as a blood-based surveillance strategy for HCC. Full article

Digital pathology and computational analysis of breast cancer require datasets that connect microscopic images with clinically meaningful diagnostic, morphological and immunohistochemical information. But images are often provided separately from pathomorphological reports, tumour profiles, biomarker assessments and segmentation masks, which limits their use for interpretable machine learning. This data descriptor presents a structured dataset of de-identified breast cancer cases that integrates H&E images, immunohistochemical images for ER, PR, HER2/neu and Ki-67, PNG cell segmentation masks and JSON-based clinical and morphological metadata. The dataset was formed from archival histological material, digitised microscopic fields of view and expert-verified diagnostic information. Each JSON record links the patient-level description, tumour profile, staining type, image file, mask file and marker-specific assessment, including Allred score fields for relevant immunohistochemical images. The proposed structure provides traceability from the diagnostic conclusion to individual image fields and associated masks. The dataset is intended to support research on tumour classification, cell segmentation, immunohistochemical marker quantification, HER2-related image analysis, Allred score modelling and explainable artificial intelligence in computational pathology. Full article

Background and Objectives: Non-small cell lung cancer (NSCLC) comprises biologically distinct histologic subtypes, including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We evaluated whether the prognostic association of cyclin-dependent kinase-like 2 (CDKL2) differs by histology. Materials and Methods: TCGA CDKL2 expression was linked to harmonized clinical data. The primary analysis used a pooled multivariable Cox model with continuous standardized CDKL2 expression, histology, and a CDKL2 × histology interaction, adjusted for age, sex, pathologic stage, and smoking. Additional analyses assessed model assumptions, tumor purity, tumor-versus-normal expression, KEGG pathways, the tumor microenvironment, and single-cell RNA sequencing. External evaluation used GSE30219. Results: The primary TCGA cohort included 943 patients (471 LUAD, 472 LUSC; 375 deaths). Higher CDKL2 expression was associated with lower mortality in LUAD (HR per 1 pooled SD = 0.721, 95% CI 0.603–0.862, p < 0.001) but higher mortality in LUSC (HR = 1.237, 95% CI 1.011–1.515, p = 0.039), with a significant interaction (HR = 1.717, p < 0.001) persisting after tumor-purity adjustment. CDKL2-low tumors were enriched for cell-cycle, DNA-replication, proteasome, and DNA-repair programs. Single-cell analyses showed predominant epithelial detection and greater malignant-cell CDKL2 detection in LUAD. In GSE30219, the favorable LUAD association was supported in a median-split-adjusted analysis of 207073_at (HR = 0.473, 95% CI 0.250–0.897, p = 0.022), whereas the corresponding continuous estimate was directionally favorable but nonsignificant; 236331_at was nonsignificant in both models; neither probe supported the adverse LUSC association or histology interaction. Conclusions: Higher CDKL2 expression showed a favorable prognostic association in LUAD, with consistent TCGA sensitivity analyses and limited but suggestive independent-cohort support. The adverse LUSC association remains preliminary, and CDKL2 should be regarded as a candidate prognostically associated marker rather than an established clinical biomarker. Full article

Ganoderma lucidum’s anticancer potential is largely attributed to its polysaccharides, yet their preclinical translation requires rigorous systematization. Following PRISMA 2020 guidelines, this systematic review evaluated the anticancer efficacy of G. lucidum polysaccharides (GLPs) in preclinical models (PROSPERO: CRD42021296200). Systematic searches spanning 2011 to 2026 were conducted in PubMed, Embase, and Scopus. Eligible peer-reviewed articles investigated GLPs in cancer cell lines or animal models. The Cochrane Risk of Bias 2 (RoB 2.0) tool was used to assess the risk of bias for animal studies. Across 14 included studies, GLPs were primarily extracted from fruiting bodies or spores via hot-water extraction and ethanol precipitation. Preclinical models predominantly involved colorectal cancer cell lines (HCT-116, HT-29, LoVo, SW480) and BALB/c, ICR, or Swiss albino mouse strains. GLPs consistently reduced tumor volume in vivo and decreased tumor cell viability in vitro. Mechanistic outcomes encompassed the induction of apoptosis, senescence, and immunomodulatory markers, frequently converging on MAPK/NF-κB signaling pathways. However, a major methodological limitation was the widespread negligence or superficiality in the chemical characterization of the tested fractions; only one study achieved complete purification of a β-D-glucan. In conclusion, while GLPs demonstrate potent tumor-suppressive and immunomodulatory properties, the pervasive structural ambiguity and lack of extract purification profoundly hinder translational reliability and the establishment of robust structure–activity relationships. Full article

Background: Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality, and responses to immune checkpoint blockade are often limited. Casein kinase 2 beta (CK2beta), encoded by CSNK2B, has established tumor-intrinsic functions, but its relationship with immune states in HCC remains unclear. Methods: We integrated TCGA-LIHC, six GEO cohort-platform combinations, GSE149614 single-cell RNA sequencing data, CIBERSORTx deconvolution, broad-compartment CellChat inference, and public proteomic resources. We evaluated CSNK2B expression, overall survival, a prespecified GDF15-associated Treg/checkpoint transcriptional module, tumor microenvironment features, compartment-level localization, and protein-level support. Results: CSNK2B was upregulated in TCGA-LIHC and all six external cohort-platform comparisons but was not a robust prognostic marker. The strongest immune association was with the GDF15-associated Treg/checkpoint module (Spearman rho = 0.371, q = 2.9 × 10⁻¹²); the direction was positive in all six GEO analyses and four passed BH-FDR. Deconvolution results were small and heterogeneous. CSNK2B and GDF15 were most prominent in hepatocyte-like compartments, while the candidate hepatocyte-to-T/NK GDF15–TGFBR2 pair was not reproduced in pooled data or in any of 10 patient-stratified CellChat runs. Public proteomic datasets supported tumor-side elevation of both proteins. Conclusions: CSNK2B expression aligns with a reproducible GDF15-associated transcriptional state in HCC, accompanied by selective stromal, endothelial, and immune-context changes. The evidence is associative and provides hypotheses for perturbation, spatial, and co-culture validation rather than a causal or treatment-prediction claim. Full article

Background/Objectives: Anal squamous cell carcinoma (SCCA) is a rare Human Papillomavirus (HPV)-related disease in the general population but its incidence is increasing among high-risk populations, i.e., men who have sex with men (MSM), HIV+ patients and women with a history of cervical/vulvar dysplasia. The objectives of this study were: (i) to investigate the prevalence of high-risk (HR) and low-risk (LR) anal HPV infections in a high-risk cohort; (ii) to correlate specific HPV genotypes with cytological and histological outcomes; and (iii) to assess the impact of cumulative HPV genotype burden. Methods: A retrospective study (2017–2022) was conducted on 550 high-risk patients. All patients underwent anal Pap tests (ThinPrep, Hologic) and HPV genotyping (Anyplex II HPV 28, Seegene), according to our screening protocol. High-Resolution Anoscopy (HRA) was performed on 430 patients; biopsy was performed in all cases with suspicious lesions. Results: The overall HR-HPV prevalence was 57.3%. Men showed a significantly higher prevalence of HR-HPV (59.9% vs. 47.4%) and cytological abnormalities (35.8% vs. 20.2%) compared to women. Notably, HPV 16, 58 and 45 accounted for 79% of AIN2+ (Anal Intraepithelial Neoplasia of grade 2 or higher) lesions. A significant cumulative HPV genotype burden effect, i.e., the number of HPV genotypes detected, was observed: patients with ≥3 HR-HPV types showed an increased risk of AIN2+ lesions (aOR 34.72; 95% CI 4.07–296.10) and AIN1+ lesions (aOR 16.26; 95% CI 4.54–58.30) respectively. The presence of ≥3 LR-HPV genotypes in HR-HPV-positive patients is associated with an increased risk of AIN1 lesions. Conclusions: HPV 16, 58 and 45 positivity and the cumulative HPV genotype burden could represent new potential indicators for risk stratification in high-risk populations. Future larger-scale prospective studies are needed to validate these preliminary results. Full article

Neuroendocrine prostate cancer (NEPC) is characterized by androgen receptor (AR) independence and poor response to conventional therapies, highlighting the need to unveil the molecular mechanisms behind NEPC. We previously showed that heme oxygenase 1 (HO-1, encoded by HMOX1) translocates to the nucleus exerting unexplored non-canonical functions. The present study delineates the nuclear interactome of HO-1, revealing a potential mechanism that impairs NEPC establishment. Through a proteomics approach integrated with bioinformatics analyses, we identified eleven novel nuclear interactors of HO-1. Unsupervised clustering analyses of RNA-seq data from prostate cancer (PCa) patient-derived xenografts (MDA PCa PDXs) and clinical cohorts demonstrated high expression of three HO-1 interactors (ILF3, SAFB, BCLAF1, and DDX17) in NEPC samples, with concomitant HMOX1 under-expression. Spatial transcriptomics in a mixed-histology tumor confirmed enrichment of the interactors in the NEPC foci. To better understand the link between HO-1 and NEPC, we established and characterized an in vitro model of NE transdifferentiation in PCa cell lines using forskolin to induce phenotypic reprogramming. HO-1 upregulation in transdifferentiated cells significantly attenuated the expression of NE markers and triggered a morphological shift, restoring epithelial phenotypes. This work identifies for the first time HO-1 nuclear interactome association with NEPC, where the HMOX1-ILF3-SAFB-BCLAF1-DDX17 print emerges as a useful marker for disease stratification. Full article