Search Results (1,945)

Background: Comprehensive genomic profiling (CGP) is a tool used in precision oncology to identify genomic alterations and match them with targeted therapies across several tumor types. However, real-world data on its clinical utility and impact remains limited. The FRONTAL study (Foundation Medicine Real wOrld evideNce in porTugAL) is a multicenter academic initiative that established a national registry of Portuguese patients with solid tumors who underwent CGP with FoundationOne CDx, Liquid CDx or FoundationOne Heme assays. Methods: Eligible patients had advanced solid tumors not suitable for curative treatment at the time of recruitment. Prior CGP testing was permitted if taken within 12 months before study initiation. Genomic profiling data were extracted from FoundationOne Medicine reports, and clinical information was extracted from medical records. Actionable alterations were defined as those associated with approved treatments or with clinical evidence of benefit in other cancers, per NCCN guidelines. Variant interpretation was also reviewed according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) guidelines. The primary outcome was disease control at 16 weeks, defined by the absence of progression. Results: The study included 205 patients between 2020 and 2025 across 10 sites, with colorectal (40, 19.5%), sarcomas (28, 13.7%), and other gastrointestinal tumors (22, 10.7%) being the most common pathologies. Actionable alterations were identified in 104 cases (50.7%). Genomic findings guided therapy decisions in 50 patients (24.4%), of whom 30 achieved disease control at 16 weeks (14.6%). Conclusions: The FRONTAL study highlighted the clinical relevance of CGP in advanced solid tumors. Over half of the patients had actionable alterations, a quarter had therapy changes based on CGP results, and improved disease outcome was observed in approximately 15% of the cohort. Full article

Endometrial cancer (EC) is the most common gynecological cancer in developed countries, with approximately 417,000 new cases reported worldwide in 2020. Its incidence has been rising for the past 30 years, primarily due to population aging, obesity, and type 2 diabetes; obesity accounts for almost half of cases due to excessive estrogen production. The classic division into types I and II was replaced in 2013 by the molecular TCGA classification, which distinguishes four subtypes: POLE-ultramutated (best prognosis), MSI-hypermutated, copy-number low, and copy-number high (worst prognosis). This classification (refined in ProMisE and TransPORTEC) enables precise treatment: immunotherapy (pembrolizumab, dostarlimab) works excellently in dMMR/MSI-H tumors, PI3K/AKT/mTOR inhibitors and trastuzumab deruxtecan in selected molecular subtypes, and hormone therapy in ER-positive tumors. ctDNA monitoring supports therapeutic decisions. Integrating the molecular profile with FIGO allows for truly personalized treatment, although MMRp/MSS tumors remain a challenge. The future lies in multi-omics, new biomarkers, and combination therapies. Full article

Despite the introduction of novel therapeutic options, the prognosis of advanced endometrial cancer remains poor. In recent years, increasing attention has been directed toward the molecular characterization of endometrial cancer. However, data specifically focusing on advanced-stage disease are still limited. In our single-center, retrospective, exploratory study with a limited sample size, we analyzed 32 patients with advanced or recurrent endometrial cancer treated at the Modena Cancer Center. Comprehensive molecular profiling was performed to assess DNA mutations, copy number variations, and RNA expression. We characterized the molecular landscape of this cohort, evaluated selected genomic alterations across predefined clinical subgroups, and explored their association with overall survival. Consistent with previous reports, a high prevalence of PTEN and PIK3CA mutations were observed. Patients experiencing relapse more than six months after diagnosis were more likely to harbor CTNNB1 mutations. KRAS mutations were more frequently detected in younger patients and in those with endometrioid histology, whereas PPP2R1A and TP53 mutations were enriched in tumors with non-endometrioid histology. Notably, CTNNB1 mutations were associated with a favorable prognostic impact, while KRAS mutations correlated with poorer overall survival. Our findings underscore the need for further investigation into the molecular landscape of advanced endometrial cancer, particularly in the context of therapeutic implications. Combinatorial treatment strategies targeting specific molecular alterations, such as KRAS, in combination with other targeted agents or therapeutic approaches, warrant further exploration. Full article

Background: Early recognition of renal allograft dysfunction requires biochemical markers capable of detecting molecular injury before functional decline becomes apparent. Serum creatinine, a late and nonspecific indicator of renal function, has limited value for early diagnosis. Protein biomarkers implicated in tubular injury, inflammation, and immune activation—including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), β2-microglobulin, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α)—have emerged as promising alternatives. This study evaluated early post-transplant serum profiles of these biomarkers and their prognostic relevance for long-term graft outcomes. Methods: Nineteen adult recipients undergoing primary kidney transplantation were prospectively enrolled. Serum creatinine and protein biomarkers were measured 24 h post-transplant using validated immunochemical assays. Biomarker concentrations were compared with values from healthy controls, and correlations with renal function at 12 months were assessed. Receiver operating characteristic (ROC) analysis was used to evaluate predictive performance. Results: Significant biochemical alterations were observed at 24 h post-transplant. KIM-1 levels were markedly elevated compared with controls (74.50 ± 98.45 vs. 10.54 ± 17.19 ng/mL; p = 0.01), consistent with early tubular injury. IL-1β and NGAL showed upward trends without reaching statistical significance. β2-microglobulin and TNF-α levels did not differ substantially from control values. Serum KIM-1 correlated with serum creatinine both at 24 h (r = 0.35) and at 12 months (r = 0.40). ROC analysis identified a KIM-1 threshold of 24.5 ng/mL (AUC = 0.68) as a potential indicator of future graft dysfunction, outperforming serum creatinine (AUC = 0.64). Six patients experienced graft dysfunction at 12 months post-transplant, five of whom had serum creatinine values > 5 mg/dL at 24 h. Based on early creatinine levels, patients were stratified into low-risk (creatinine < 5 mg/dL; n = 10) and high-risk groups (creatinine > 5 mg/dL; n = 9). Mean KIM-1 concentrations were significantly higher in the high-risk group (110.68 ± 115.29 vs. 26.67 ± 18.05 ng/mL; p = 0.05), consistent with more severe early tubular injury. Conclusions: Among the evaluated biomarkers, KIM-1 demonstrated the strongest potential as an early biochemical indicator of renal allograft dysfunction. Its rapid post-transplant elevation underscores its sensitivity to early tubular injury. Further prospective validation in larger, multicenter cohorts is warranted. Full article

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an immune-mediated neurological disorder driven by dysregulated neuroimmune interactions, yet the molecular architecture linking tumor-associated immune activation, peripheral immunity, and neuronal dysfunction remains insufficiently understood. In this study, we established an integrative computational framework that combines multi-tissue transcriptomic profiling, weighted gene co-expression network analysis, immune deconvolution, and machine learning-based feature prioritization to systematically characterize the regulatory landscape of the disease. Joint analysis of three independent GEO datasets spanning ovarian teratoma tissue and peripheral blood transcriptomes identified 2001 consistently dysregulated mRNAs, defining a shared tumor–immune–neural transcriptional axis. Across multiple feature selection algorithms, ACVR2B and MX1 were reproducibly prioritized as immune-associated candidate genes and were consistently downregulated in anti-NMDAR encephalitis samples, showing negative correlations with neutrophil infiltration. Reconstruction of an integrated mRNA-miRNA-lncRNA regulatory network further highlighted a putative core axis (ENSG00000262580–hsa-miR-22-3p–ACVR2B), proposed as a hypothesis-generating regulatory module linking non-coding RNA regulation to immune-neuronal signaling. Pathway and immune profiling analyses demonstrated convergence of canonical immune signaling pathways, including JAK-STAT and PI3K-Akt, with neuronal communication modules, accompanied by enhanced innate immune signatures. Although limited by reliance on public datasets and small sample size, these findings delineate a systems-level neuroimmune regulatory program in anti-NMDAR encephalitis and provide a scalable, network-based multi-omics framework for investigating immune-mediated neurological and autoimmune disorders and for guiding future experimental validation. Full article

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors primarily involving the adrenal medulla and its associated paraganglia, with heterogeneous clinical behavior and complex molecular drivers. This study aimed to characterize DNA methylation and gene expression patterns in PPGLs to understand the molecular differences between tumor subtypes and malignancy. We performed an integrative analysis of DNA methylation (Illumina EPIC 850K) and gene expression profiles (Affymetrix microarrays) in 24 PPGLs, comparing these with The Cancer Genome Atlas (TCGA) data, to delineate cluster- and malignancy-specific epigenetic patterns. Comparison between pseudohypoxic Cluster I and kinase-signaling Cluster II tumors revealed 13 differentially methylated CpG sites, with a specific CpG within DSCAML1 showing hypermethylation in Cluster II accompanied by increased expression, suggesting context-dependent gene body methylation effects. Benign versus malignant comparisons identified 101 differentially methylated CpGs, including hypermethylated CpG in BAIAP2L1 and hypomethylated CpG in SHANK1 in malignant tumors. Pathway enrichment of differentially methylated genes revealed alterations in Notch signaling, adherens junctions, cytoskeletal regulation, and intracellular transport. Gene expression analysis demonstrated partial overlap between clusters, with malignant tumors exhibiting distinct transcriptional profiles involving RNA processing, metabolism, and adhesion pathways. Correlation between methylation and expression was generally limited, emphasizing that methylation-dependent gene regulation is a locus-specific and context-dependent regulation. These findings illustrate a complex interplay between epigenetic modifications and transcriptional programs in PPGLs, enhancing our understanding of molecular heterogeneity and tumor classification, and identifying candidate biomarkers and therapeutic targets for malignant progression. Full article

Early weaning in intensive lamb production improves reproductive efficiency but predisposes lambs to diarrhea, oxidative stress, and intestinal barrier dysfunction, highlighting the need for non-antibiotic strategies to protect gut health. This study evaluated whether a sheep-derived mixed probiotic could alleviate early weaning–induced intestinal injury and clarified its potential molecular mechanisms. Early weaning reduced body weight, average daily gain and feed efficiency, increased diarrhea, decreased plasma and colonic catalase (CAT), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) activities, increased malondialdehyde (MDA), elevated interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), reduced interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), increased plasma and mucosal immunoglobulin A, M, and G (IgA, IgM, IgG), and increased colonic lipopolysaccharide (LPS) with reduced diamine oxidase (DAO). Intestinally, EW induced villus atrophy, deeper crypts, lower villus height-to-crypt depth ratios, goblet cell loss, higher histopathological scores, and decreased colonic mucin 2, zonula occludens-1, claudin-1, and occludin. Probiotic supplementation partially reversed these alterations, restoring antioxidant enzyme activities, improving villus architecture and barrier protein expression, and rebalancing cytokine and immunoglobulin profiles. Transcriptomic and network analyses showed that early weaning activated Cytokine–cytokine receptor, NF-κB, TNF and Th17 pathways, whereas probiotics suppressed a weaning-responsive inflammatory gene module, downregulated key hub genes, and enhanced peroxisome proliferator-activated receptor (PPAR) signaling. These results show that supplementing early-weaned lambs with a mixed probiotic generated from sheep is an efficient nutritional strategy to reduce intestinal oxidative and inflammatory damage associated with weaning and to enhance their health and performance. Full article

Recurrent endometrial cancer (EC) has limited therapeutic options beyond platinum-based chemotherapy, highlighting the need to identify exploitable molecular vulnerabilities. Tumors with high genomic instability, including microsatellite instability-high (MSI-h) or copy-number-high (CNH) ECs, rely on the ATR-CHK1 signaling pathway to tolerate replication stress and maintain genome integrity, making this pathway an attractive therapeutic target. However, acquired resistance to ATR and CHK1 inhibitors (ATRi/CHK1i) often develops, and the transcriptomic basis of this resistance in EC remains unknown. Here, we established isogenic ATRi- and CHK1i-resistant cell line models from MSI-h (HEC1A) and CNH (ARK2) EC lineages and performed baseline transcriptomic profiling to characterize stable resistance-associated states. MSI-h-derived resistant clones adopted a unified transcriptional state enriched for epithelial-mesenchymal transition, cytokine signaling, and interferon responses, while ATRi-resistant models showing additional enrichment of developmental and KRAS/Notch-associated pathways. In contrast, CNH-derived resistant clones diverged by inhibitor class, with ATRi resistance preferentially enriching proliferation-associated pathways and CHK1i resistance inducing interferon signaling. Notably, THBS1, EDN1, and TENM2 were consistently upregulated across all resistant models relative to parental lines. Together, these findings demonstrate that acquired resistance to ATRi and CHK1i in EC is shaped by both lineage and inhibitor class and provide a transcriptomic framework that may inform future biomarker development and therapeutic strategies. Full article

Endometriosis (EM) is a chronic inflammatory disease characterized by the growth of endometrial-like tissue outside the uterus, yet its molecular mechanisms remain poorly understood. This study investigated the expression of mucins (MUC1, MUC2, MUC5AC, MUC6, MUC16) and their O-glycans in endometriotic lesions, given their roles in epithelial protection, adhesion, and immune modulation. Using immunohistochemistry, Western blotting, lectin profiling, histochemical staining, and transcriptomic analysis, we compared mucin levels and glycosylation patterns in eutopic and ectopic tissues from women with and without endometriosis and measured mucin-derived tumor markers in serum (CA 125/MUC16 and CA 15-3/MUC1) and peritoneal fluid (CA 125/MUC16). The results showed significant upregulation of all mucins in EM biopsies, with increased MUC1 transcript levels, while MUC6 and MUC16 protein levels did not always align with transcripts. Yet, tumor markers CA 125 and CA 15-3 showed no significant differences between groups. Looking at mucin distribution in biopsies of peritoneal (pEM), deep infiltrating and ovarian EM, MUC1 was significantly overexpressed in lesions of all EM forms, while MUC5AC was significantly elevated in pEM. Lectin analysis revealed specific glycan changes, including elevated core-1 O-glycans and α(1-2)-linked fucosylation, while sialylation remained unchanged. These findings demonstrate consistent mucin dysregulation and glycan alterations, implicating their roles in epithelial adhesion, immune evasion, and lesion persistence. Mucin biology thus emerges as a promising target for diagnostic and therapeutic strategies in endometriosis. Full article

Hydroxyprogesterone (HP) is a synthetic progestogen widely used in obstetric care, and its potential influence on breast cancer biology has become an emerging area of interest. Despite its clinical use, the molecular mechanisms by which HP affects tumor tissue remain insufficiently explored. In this study, transcriptomic profiling was performed to investigate gene expression changes associated with HP in operable breast cancer. Pre-operative 17α-HP caproate (17-OHPC) exposure was associated, in normal adjacent tissue (NAT), with activation of steroid-hormone and lipid/xenobiotic-metabolism programs and crosstalk to phosphoinositide 3-kinase (PI3K)–Akt and nuclear factor kappa B (NF-κB). In NAT, these pathways showed the largest absolute log₂ fold-change (|log₂FC|); significance is reported as false discovery rate (FDR) throughout (e.g., FKBP5↑ with HP). In tumor tissue, the dominant signal reflected tight-junction/apical-junction and extracellular matrix (ECM)-receptor remodeling (e.g., CLDN4↑). We prioritized FKBP5 (HP pharmacodynamics) and CLDN4 (tumor baseline) as the main candidates; TSPO and SGK1 are reported as exploratory. This discovery-level, hypothesis-generating analysis nominates candidate biomarkers and pathway signals for prioritization and evaluation in independent datasets and future studies. These findings provide mechanistic insight into HP’s molecular effects in breast cancer and suggest potential applications in biomarker perioperative management. Full article

Precise molecular characterization of glioblastoma (GB) is fundamental for accurate risk stratification and therapeutic planning. DNA methylation profiling reliably identifies key molecular features, including O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and specific molecular subtypes, such as receptor tyrosine kinase (RTK) I and II, and the mesenchymal (MES) subtype. In this study, we investigated the hypothesized correlation between these molecular profiles and preferential tumor locations, which could reveal a link to underlying tumor biology. We analyzed 227 GB patients characterized by DNA methylation profiling. To map significant clusters of tumor occurrence across subtypes and subcomponents, we performed voxel-wise analysis of differential involvement, utilizing 500 permutations to correct for multiple comparisons. While uncorrected frequency differential maps suggested localization tendencies for the RTK I, RTK II, and MES subtypes, stringent statistical correction revealed only one robust association: the non-enhancing component of MES tumors showed significant clustering in the left frontal lobe, the insula, and the temporal lobe. Contrary to prior literature, we observed no significant hemispheric preference regarding MGMT promoter methylation status. Our findings challenge prior assumptions regarding the spatial distinctiveness of GB subtypes and highlight the need to further elucidate the mechanisms governing tumorigenesis and spatial growth patterns. Full article

Isothiocyanates (ITCs) are well-known electrophilic agents with antioxidant and anticancer properties, largely attributed to their ability to activate the Nrf2/ARE pathway. Building on previous work with C1-ITC glycosyl derivatives, we designed and synthesized a new series of S-glycosyl isothiocyanates in which the ITC group was repositioned to the C6 carbon of the glucose scaffold. This structural rearrangement yielded stable and synthetically accessible derivatives with markedly enhanced biological profiles. Several compounds showed potent Nrf2 activation at non-cytotoxic concentrations, with CD values comparable to or exceeding those of natural ITCs. In parallel, the new C6-ITC derivatives displayed significant antiproliferative activity against leukemia and solid tumor cell lines. Among them, the phenylsulfone derivative 13 emerged as a particularly promising dual-action molecule, combining strong Nrf2 induction with low-micromolar cytotoxicity. Molecular docking was used as a hypothesis-generating approach and suggested a possible interaction with the STAT3 SH2 domain, although further studies are needed to validate this target. Overall, these results support glucose-based ITCs as a versatile platform for the development of multifunctional antioxidants with complementary anticancer properties. Full article

High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive form of epithelial ovarian cancer and is characterized by high recurrence rates and poor clinical outcomes. In this study, we identify molecular signatures associated with recurrence by conducting integrative transcriptomic and proteomic analyses on paired primary and recurrent HGSOC tissues from 34 patients. RNA sequencing and proteomic profiling revealed 185 differentially expressed genes (DEGs) and 36 differentially expressed proteins (DEPs) linked to recurrence. Pathway enrichment and Ingenuity pathway analyses highlighted the involvement of immune cell trafficking, cell signaling, and MAPK pathway activation in recurrent tumors. A survival analysis identified seven DEGs that correlated significantly with recurrence-free survival; among them, IL7R, IRF8, and PTPRC were upregulated in recurrent tumors and associated with poor prognosis, and NSG1 was downregulated and linked to favorable outcomes. Immunohistochemistry validated the differential expression of these markers at the protein level. The proteomic analysis demonstrated that recurrent tumor-specific DEGs are functionally linked to MAPK signaling. Co-expression analyses revealed dynamic regulatory interactions between the DEGs and DEPs, suggesting context-dependent molecular shifts during recurrence. This integrative multi-omics approach reveals that key molecular alterations underlie HGSOC recurrence and identifies IL7R, IRF8, PTPRC, and NSG1 as potential prognostic biomarkers and therapeutic targets. Our findings provide a foundation for targeted strategies to improve outcomes for patients with recurrent HGSOC. Full article

Background: Sarcomas are rare, aggressive malignancies with limited therapeutic options in advanced stages. This is the first real-world study in the MENA region evaluating the clinical utility of Next-Generation Sequencing (NGS) in guiding sarcoma treatment and improving outcomes. Methods: We retrospectively reviewed sarcoma patients who underwent NGS at a major referral center (2021–2024), comparing clinical and molecular outcomes between those who received NGS-based treatment adjustments (NBTA) and those who did not. Results: Seventy-eight patients were included (60% male; median age 44 years). Soft tissue sarcomas accounted for 70.5% of cases (n = 55), while bone sarcomas represented 29.5% (n = 23). Prior to NGS, 64.1% of patients had received a median of one line of systemic therapy. NGS was performed late in the disease course in 73% of cases. At least one mutation was detected in 87% (median 3 mutations). Targetable alterations were identified in 33% at the time of testing, rising to 42% with updated genomic knowledge and therapeutic advances. Overall, 20.5% received NBTA. Among non-NBTA patients, 67% had no actionable targets, 17% had no detectable mutations, and 16% were ineligible due to cost, limited access, or clinical deterioration. Tumor Mutational Burden was low in 79%, intermediate in 19%, and high in 2%, and all tumors were microsatellite stable. Patients receiving NBTA had a longer median Progression-Free Survival (9 vs. 2 months; p = 0.023). Median Overall Survival was longer in the NBTA group (74 vs. 48 months), though not statistically significant (p = 0.207). Genomic alterations were subtype-specific: EWSR1 rearrangements (Ewing and Desmoplastic small round cell tumors), CDK4 and MDM2 amplifications (Liposarcoma and Osteosarcoma), TP53 and RB1 mutations (Leiomyosarcoma), CDKN2A/B deletions (Undifferentiated Pleomorphic Sarcoma and Chondrosarcoma), and SS18 rearrangements (Synovial Sarcoma). Conclusions: Genomics-guided therapy in sarcoma is feasible and impactful. Expanding timely access to molecular profiling is essential for advancing precision oncology in the MENA region. Full article

Liver cancer, also known as hepatocellular carcinoma (HCC), remains a major global health concern, with high mortality driven by late-stage diagnosis, limited treatment efficacy, and frequent therapeutic resistance. Matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, are central to the biological processes that drive liver tumor initiation and progression. By degrading and reorganizing extracellular matrix components, MMPs facilitate tumor expansion, tissue invasion, and metastatic dissemination. In addition, these enzymes regulate the availability of growth factors, cytokines, and chemokines, thereby influencing angiogenesis, inflammation, immune cell recruitment, and the development of an immunosuppressive tumor microenvironment. Aberrant expression or activity of multiple MMP family members is consistently associated with aggressive clinicopathologic features, including vascular invasion, increased metastatic potential, and reduced patient survival, highlighting their promise as prognostic markers and actionable therapeutic targets. Past attempts to modulate MMP activity were hindered by broad inhibition profiles and dose-limiting toxicities, underscoring the need for improved specificity and delivery strategies. Recent advances in molecular design, biologics engineering, and nanotechnology have revitalized interest in MMP targeting by enabling more selective, context-dependent modulation of proteolytic activity. Preclinical studies demonstrate that carefully tuned MMP inhibition can limit tumor invasion, enhance anti-angiogenic responses, and potentially improve the efficacy of existing systemic therapies, including immuno-oncology agents. This review synthesizes current knowledge on the multifaceted roles of MMPs in HCC pathobiology and evaluates emerging therapeutic strategies that may finally unlock the clinical potential of targeting these proteases. Full article