Neuro-oncology is the study of brain and spinal cord neoplasms. Molecular targets and signaling pathways are pivotal in advancing modern healthcare, particularly in personalized medicine. Signaling pathways, which regulate cellular processes such as growth, division, and survival, are frequently dysregulated in cancer. Targeting these pathways has enabled the development of personalized therapies that improve efficacy while minimizing side effects. This approach has led to significant improvements in patient outcomes, reduced treatment toxicity, and a shift toward precision medicine, driving innovation in drug discovery. The integration of molecular targets and signaling pathways into clinical practice highlights their importance for enhancing patient care.

Numerous genes have been associated with colorectal cancer (CRC) treatment in prior studies, but the impact of radiotherapy-related autophagy genes (RRAGs) on CRC remains largely unexplored. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were implemented to screen out RRAGs significantly associated with survival, and a prognostic model was constructed. Samples were categorized into high- and low-risk groups with median riskscore. Immunomicroenvironment analysis, immunotherapy response prediction, enrichment analysis, tumor mutation analysis and drug prediction were performed in risk groups. Expression of signature genes in CRC cells was examined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). There were 10 CRC-related RRAGs found. Prognostic models were built with RRAGs. Based on immune infiltration analysis, low-risk populations showed significantly greater levels of immune infiltration (P P ARHGEF17 mutation rate was 6%. Medications such as CGP-082996, Dasatinib, Erlotinib, and Salubrinal were more sensitive to high-risk group, whereas drugs such as FTI-277, DMOG, and Crizotinib were more sensitive to low-risk group. UGT1A6 and IRGM were significantly upregulated in tumor group as revealed by qRT-PCR. This study constructed a new prognostic model for CRC patients based on RRAGs, and a series of analysis results is conducive to providing more theoretical references and new insights into precision treatment of CRC patients.

Lung adenocarcinoma (LUAD) is one of the most malignant tumors with significant implications for population health and life. Nicotinamide metabolism may play a pivotal part in influencing the prognosis of LUAD. This study aimed to figure out the potential value of nicotinamide metabolism-related genes (NMRGs) in LUAD prognosis.

Targeting PI3K/AKT/MTOR (PAM) signaling pathway may be a strategy at the fore for treating lung squamous cell carcinoma (LUSC). However, relationships of PAM pathway-related genes (PAGs) with LUSC prognosis are unknown. Therefore, identifying the prognostic significance of PAGs for LUSC is innovative and feasible. Transcriptomic data, clinical features, and PAGs of LUSC were obtained from public databases (TCGA, GEO). A PAGs-based prognostic model was built using regression analysis in TCGA-LUSC. Gene levels were assessed via qRT-PCR. Predictive performance was verified through multiple datasets. Differences in immune infiltration and anti-tumor immunity between risk groups were assessed by R packages. Sensitivity to common anti-cancer agents was tested using oncoPredict package. We identified a Riskscore model containing 11 PAGs. Patients were assigned into groups of high risk (HR) and low risk (LR) per median Riskscore. CAB39L, CDKN1A, and ITPR2 were significantly underexpressed in LUSC cells. TRAF2 and TRIB3 were significantly enhanced in LUSC cells. The LR group had a longer survival time. Prognostic values of one-, three-, and five-year ROC curves were good. Results were verified in GEO. Patients in LR group had higher immune infiltration levels of B cells and Tfh cells, and higher ssGSEA scores for APC_co_inhibition and T_cell_ co_stimulation. LR group had lower TIDE scores and lower IC50 values (Alpelisib, Ibrutinib, Sapitinib, and Savolitinib). We successfully built a reliable 11-gene Riskscore prognostic model. Patients in LR group had potential advantages in survival, immune response, and drug sensitivity. In summary, the results offered new insights into prognosis prediction, immunotherapy, and personalized treatment of LUSC.

Circular RNAs (circRNAs) play a pivotal part in the advancement of multiple tumors. Nonetheless, the influence of Helicobacter pylori (H. pylori) infection on the expression of circRNA in gastric cancer remains less studied.

Minimal residual disease (MRD) is a small group of cancer cells not eliminated by anti-cancer treatment. Because of its small size, conventional imaging system may not be able to detect the MRD in routine clinical practice. Although the liquid biopsy tests can detect the circulating tumor DNA (ctDNA) when the tumor is present in the body, the fraction of ctDNA is considered lower than the 0.01% which is unreachable by current state-of-the-art liquid biopsy assay relying on fixed-gene panel approach. Here, we describe the analytical validation result of our previously developed a tumor-informed MRD test, CancerDetectTM (formerly reported as AlphaLiquid®Detect), leveraging large-scale mutation spectrum profiling strategy to enhance detection sensitivity. The CancerDetectTM is a hybrid-approach MRD test combining both personalized (bespoke) mutations and tumor-agnostic clinically actionable targets (hotspot mutations) with hybridization capture technology. The analytical validation result of CancerDetectTM showed limit of detection successfully reached down to 0.001% (10-5) with 99.9% specificity.

IntroductionImmune checkpoint inhibitors plus chemotherapy has become the new standard of care for advanced biliary tract cancer (BTC). However, the real-world effectiveness and safety of this approach, and its association with molecular alterations, remains uncertain.MethodsIn this single institutional retrospective cohort study, patients with advanced BTC treated with systemic chemotherapy with or without immunotherapy from July 2020 to June 2025 were included. Primary endpoint was overall survival (OS) in patients treated with first-line chemoimmunotherapy; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, prognostic factors, and molecular profiling.Results49 of 52 patients (94.2%) received chemoimmunotherapy. Median OS and PFS were 10.2 months and 5.4 months, respectively; the ORR was 24.5%. Poor Eastern Cooperative Oncology Group (ECOG) performance status and hypoalbuminemia were independent predictors of poor OS. Among the 52 patients, molecular profiling identified IDH1 mutations (9.6%), FGFR2 fusions (3.9%), HER2 amplification (5.8%), dMMR (5.8%), and BRCA mutations (5.8%). HER2 amplification was associated with worse OS; dMMR and BRCA mutations showed a trend toward improved OS.ConclusionReal world first-line chemoimmunotherapy for advanced BTC achieved outcomes comparable to those in pivotal trials. The ECOG performance status, serum albumin level, and HER2 status were prognostic for OS, supporting the importance of baseline patient selection and molecular profiling in treatment planning.

ObjectivesThis study aims to investigate the significance of tumor microenvironment (TME)-related genes and signal transduction pathways in head and neck cancer (HNC).MethodsGene expression and clinical data of HNC patients were obtained from the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were screened through a multi-step filtration approach to obtain candidate predictors. The biological role of COL5A1 in HNC was verified through rigorous bioinformatic analysis, experimental validation using quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) analysis from HNC samples, and IHC data from the Human Protein Atlas (HPA) database.ResultsCOL5A1 was significantly upregulated in HNC tissues and cell lines. High COL5A1 expression was significantly associated with advanced tumor grade (P < .05) and shorter survival (TCGA: P < .001; GSE42743: P = .004). COL5A1 was an independent prognostic indicator (univariate analysis: HR = 1.324, P = .001; Multivariate analysis: HR = 1.326, P = .005). It was enriched in pathways related to tumor invasion and immune responses, and its expression was associated with decreased levels of CD8+ T cells and increased levels of macrophages and neutrophils. Spatial distribution analysis revealed higher expression at the tumor's leading edge (vs. tumor core: P < .001). COL5A1 expression is associated with tumor stage, with more pronounced expression in advanced-stage tumors.ConclusionCOL5A1 represented a novel potential prognostic indicator and therapeutic target in an HNC database sample, as its expression is closely linked to tumor progression, immune cell infiltration, and adverse clinical outcomes. These findings, primarily derived from squamous cell carcinoma-dominated cohorts, warrant further functional validation.

Super-enhancers (SEs) are clusters of enhancers with potent regulatory capabilities. They play a crucial role in shaping cellular identity and driving the progression of various diseases, including cancer. SEs exhibit significant heterogeneity across different cell types and cancer subtypes. Analysis of SE landscapes can recapitulate existing classification systems and unveil novel SE-driven epigenetic subtypes. In this review, we summarized the latest advancements in cancer subtype identification based on SE-related characteristics, outlined the typical analytical workflows adopted in such studies, and explored the biological and clinical significance of SE-driven subtypes. Furthermore, we discussed the field's key challenges and emerging technologies to highlight future research directions. SE analysis provides a robust framework for dissecting cancer heterogeneity. This approach offers novel epigenetic perspectives and support for the realization of personalized medicine.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a poor prognosis, thus emphasizing the need for early and accurate diagnostic tools. In this study, we propose a comparative study approach to understand how machine learning (ML) modeling using urinary biomarkers combined with demographic data can predict PDAC. The study also utilized a single-cell RNA sequencing (scRNA-seq) analysis to assess and understand gene expressions of included biomarkers. With inclusion of available biomarkers and incorporation of demographic information, we employed different approaches for preprocessing techniques, normalization approaches, ML techniques, and deep learning (DL) approaches to provide a comprehensive prediction model. The scRNA-seq approach also highlighted the significance of the urinary biomarkers from the pancreatic single-cell sample. Based on this analysis, the marker was identified as one of the top three most highly expressed genes in PDAC tissues. The predictive modeling approach was conducted for both binary and multiclass classification using both ML and DL approaches. The comparative analysis using all included parameter combinations produced modeling settings, and among these parameters, the DL modeling approach using binary classification outperformed the other approaches by achieving 91% accuracy. This framework provided insights that highlighted the critical role of demographic data and potential approaches to include such features in the model without impacting the predictive accuracy. Future work will focus on examining the framework using different datasets, integrating additional omics data, and exploring advanced DL architectures to further improve predictive performances.

Adamantimoma-Like Ewing Sarcoma (ALES) is a rare variant of Ewing sarcoma that poses significant diagnostic challenges in the head and neck due to morphologic overlap with basaloid carcinomas and neuroendocrine neoplasms.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive endocrine malignancies, characterized by rapid progression, extensive metastasis, and extremely poor prognosis. Despite advances in molecular oncology, the mechanisms driving ATC metastasis and therapeutic resistance remain largely unclear. Cancer cells that detach from the extracellular matrix must evade a specific form of apoptosis known as anoikis, and the ability to survive under these anchorage-independent conditions is a critical prerequisite for metastatic dissemination. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a master regulator of oxidative-stress responses and tumor adaptation, yet its function in governing anoikis resistance in ATC is not well understood. Here we demonstrate that Nrf2 expression is markedly upregulated in ATC tissues and cell lines, where its nuclear translocation drives transcriptional activation of anti-apoptotic and redox-protective genes including BCL-2 and SLC7A11. Under detachment stress, Nrf2 activation enhances cell viability, inhibits apoptosis, and facilitates multicellular aggregate formation, thereby promoting survival. Conversely, genetic silencing or pharmacological inhibition of Nrf2 with Brusatol markedly suppresses proliferation, invasion, and in vivo liver metastasis. Collectively, these findings identify Nrf2 as a pivotal driver of ATC anoikis resistance and metastatic competence through regulation of the BCL-2/SLC7A11 axis. Targeting the Nrf2-dependent survival pathway may thus offer a promising therapeutic strategy for this otherwise refractory malignancy.

About 40% of non-functioning (NF) Pancreatic Neuroendocrine Tumors (PanNETs) harbour mutations in MEN1, often co-occurring with DAXX/ATRX. While the ADM group (MEN1 and DAXX/ATRX co-mutated) exhibits homogeneous genetic and epigenetic features and a consistent risk of relapse, it shows considerable variability in treatment response, suggesting an underlying molecular diversity. In this study we aimed to elucidate the molecular mechanisms underlying this heterogeneity of ADM PanNETs by integrating transcriptomic (n = 36) and DNA methylation (n = 93) data. First, DNA methylation discriminates ADM-PanNET from PanNET mutated only in MEN1 (α-like), revealing enhancer, peri-centromeric, and telomeric methylation changes associated with alternative lengthening of telomeres and increased chromosomal instability. Transcriptomic analysis further revealed three distinct ADM subtypes: ADM hypoxic, ADM NST (No Special Type), and ADM immunosuppressive. The ADM hypoxic subtype is characterized by strong hypoxia signature, likely regulated epigenetically. The ADM NST subtype appears to be primarily driven by epigenetic changes that promote proliferation. Notably, the ADM immunosuppressive subtype, although significantly smaller (< 2.5 cm, p = 0.023), exhibits strong immune and metastasis-like signatures, suggesting a uniquely aggressive biology despite its reduced size. By defining these three novel ADM subtypes, our study provides a refined framework for understanding PanNET heterogeneity. This classification underscores potential diagnostic markers and highlights distinct biological vulnerabilities that may inform the development of subtype-tailored therapeutic strategies.

Salivary gland intraductal papillary mucinous neoplasm (SG IPMN) is a recently described entity arising predominately from intraoral minor salivary glands, characterised by a low-grade papillary cystic proliferation of mucinous columnar cells, so-named due to its resemblance to the pancreatic duct counterpart [1]. It is currently mentioned in the World Health Organization (WHO) Classification of Tumours (5th edition) salivary gland tumours introduction as a lesion with low-grade mucinous morphology that shares frequent AKT1 mutations with mucinous adenocarcinoma, hence it is thought to represent a low-grade salivary gland mucinous adenocarcinoma and is currently subsumed into this entity [1-3]. However, the classification of the neoplasm remains a controversial issue, with the WHO noting that it is still not established whether SG IPMN should be classified separately or within the mucinous adenocarcinoma spectrum as a potential precursor [2].

Lung cancer continues to be a significant health burden in the United States, with 2025 estimates indicating approximately 226,650 new cases and 124,730 deaths. NSCLC is the predominant histological subtype of lung cancer, representing approximately 80% to 85% of all diagnosed cases. Within the NSCLC cohort, the EGFR represents the most commonly altered tumor-initiating mutation, exhibiting the highest prevalence among actionable molecular aberrations. Ex20ins in the EGFR gene represent the third most common type of EGFR mutation, observed in approximately 0.3% to 2.9% of all NSCLC cases and 2% to 5% of EGFR-mutant NSCLC subtypes. In July 2025, the US FDA granted accelerated approval for sunvozertinib, an oral and irreversible EGFR tyrosine kinase inhibitor, for the treatment of NSCLC patients who have mutations in the EGFR Ex20ins. Sunvozertinib received conditional approval in China for the second-line NSCLC with mutations in the EGFR Ex20ins, based on safety and efficacy data derived from a Phase II clinical study. Before the approval of sunvozertinib, treatment approaches for EGFR Ex20ins-mutant patients with NSCLC were limited and largely suboptimal. Conventional EGFR-TKIs exhibited minimal clinical efficacy, primarily due to intrinsic structural resistance mechanisms conferred by these specific mutations. This manuscript focuses on the clinical studies that supported the USFDA accelerated approval of sunvozertinib, along with its ongoing and upcoming clinical trials, preclinical research, and other pharmacological aspects.

Rapid early progression (REP) is defined as MRI progression of glioblastoma after surgical resection before adjuvant therapy. REP occurs in approximately 50% of glioblastoma and is associated with worse overall survival. Despite the increasing trend towards molecular characterization of glioblastoma, no analysis has been performed between molecular alterations in glioblastoma and REP that may help define the urgency of adjuvant therapy.

Mesenchymal stem cell-derived exosomes (BM-MSC-Exos) have attracted increasing interest for their potential to modulate leukemic cell behavior in acute myeloid leukemia (AML). In this study, the effects of BM-MSC-Exos on the AML cell line THP-1 were evaluated. A dose-dependent reduction in cell viability was observed after 24 h of treatment, as determined by MTT assay. Flow-cytometric analysis revealed a significant increase in apoptotic activity following exposure to BM-MSC-Exos. Cell cycle analysis demonstrated an accumulation of cells in the G0/G1 phase, consistent with growth arrest. Gene-expression profiling by real-time PCR showed upregulation of pro-apoptotic genes (Caspase3, Caspase9, BID, and BAX) and downregulation of the anti-apoptotic gene BCL2. Likewise, expression of cell cycle regulators such as Cyclin D1 and CDK6 was reduced. Importantly, TUG1, an oncogenic long non-coding RNA implicated in leukemogenesis, was also significantly downregulated in exosome-treated cells. Taken together, these results may shed light on the possible role of BM-MSC-Exos in regulating apoptosis, cell-cycle progression, and TUG1 expression in leukemic cells. Further studies are warranted to elucidate the molecular mechanisms underlying these effects and to determine how BM-MSC-Exos-mediated modulation of TUG1 might contribute to leukemic cell regulation.

Germline pathogenic variants within the highly conserved exonuclease domain of the POLD1 gene predisposes to colorectal (CRC) and endometrial (EC) cancers. Tumours with POLD1-deficiency demonstrate unique genomic features including hypermutation and tumour mutational signatures (TMS) SBS10c, SBS10d and SBS20. The classification of variants within POLD1 remains challenging. The utility of incorporating tumour hypermutation status and TMS profiles into POLD1 gene-specific variant classification guidelines developed by ClinGen-InSiGHT remains to be established. We report a family with eight members heterozygous for the germline POLD1 c.1420C > A (p.Leu474Ile) variant. This variant resides within the exonuclease domain, is absent in gnomADv4.1 and is classified as a variant of uncertain clinical significance. Formalin-fixed paraffin embedded tissue and matched blood-derived DNA from person 001 (EC, 1 adenoma, 2 sessile serrated lesions), and two cousins, 009 (EC, 3 adenomas), and 010 (breast cancer, EC, CRC, 4 adenomas, 2 sessile serrated lesions and 1 traditional serrated adenoma) were tested using a custom multigene panel to determine tumour mutational burden (TMB) and TMS. All three ECs demonstrated characteristics of POLD1-deficiency namely hypermutated TMB and predominance of SBS10d. The CRC, 62.8% of the adenomas and 60% of the serrated polyps demonstrated SBS10c as the dominant TMS. EC, CRC, breast and multiple polyps from three family members heterozygous for the germline POLD1 c.1420C > A variant demonstrated hypermutation and SBS10c and SBS10d TMS, genomic features associated with defective POLD1. Somatic TMB and TMS profiling of multiple independent lesions demonstrated utility for identifying POLD1-deficiency suggesting this approach can support variant classification for POLD1.

Epigenetic dysregulation plays a critical role in colorectal cancer (CRC) progression. Our study investigated the role of FAM111B in tumorigenic phenotypes and ferroptosis in CRC and the mechanisms by which epigenetic alterations influence FAM111B expression. Bioinformatics analyses revealed FAM111B expression and predicted the association between IGF2BP2 and FAM111B or ELF1. The influence on cell phenotypes was determined by assessing cell proliferation, migration, apoptosis and ferroptosis. Mechanism analyses were performed using luciferase reporter and ChIP assays. Subcutaneous xenografts were used to evaluate the role in vivo. FAM111B, IGF2BP2 and ELF1 were upregulated in CRC tumours and cell lines. FAM111B downregulation inhibited cell proliferation and migration while inducing apoptosis and ferroptosis. IGF2BP2 increased FAM111B expression by stabilising its mRNA, and ELF1 transcriptionally upregulated IGF2BP2. Moreover, ELF1 modulated FAM111B expression through IGF2BP2. ELF1 knockdown suppressed cell proliferation and migration while triggering apoptosis and ferroptosis, which could be abolished by reintroduction of IGF2BP2 or FAM111B. Additionally, ELF1 depletion diminished the in vivo tumorigenicity of HCT116 cells. The ELF1/IGF2BP2/FAM111B cascade drives CRC progression and ferroptosis resistance. Targeting this cascade may provide a therapeutic avenue for CRC treatment.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with a poor prognosis and limited effective treatment options. Our study comprehensively explores the complex role of programed cell death (PCD) mechanisms in PDAC development, examining 18 distinct PCD pathways and their genetic underpinnings. Using an advanced machine learning framework incorporating 429 algorithmic variations, we have developed an innovative PCD-based molecular signature that demonstrates robust prognostic capabilities. This signature exhibits superior performance across diverse patient cohorts, significantly outperforming traditional clinicopathological indicators. Through integrated pathway analysis, we revealed that high-risk patients show distinct activation of oncogenic pathways and significant alterations in the tumor immune microenvironment. These alterations include reduced infiltration of cytotoxic T lymphocytes and increased levels of immunosuppressive regulatory T cells (Tregs). Furthermore, leveraging the TISCH (Tumor Immune Single Cell Hub) database, we conducted detailed single-cell expression profiling of our signature genes across different cell populations within the tumor microenvironment (TME). This analysis uncovered cell-type-specific expression patterns of key PCD-related genes. Our results highlight the critical involvement of PCD in PDAC progression and introduce a promising tool for clinical risk stratification. The integration of bulk and single-cell transcriptomic analyses not only validates our molecular signature but also reveals potential cellular targets for therapeutic intervention. This PCD-focused approach may support the development of personalized therapeutic strategies and ultimately improve outcomes for PDAC patients.