Cholangiocarcinoma (CHOL) is a highly fatal malignancy originating from the bile ducts, with most patients diagnosed at an advanced stage, limiting treatment options. This study explores the role of Muscleblind-like 3 (MBNL3), a conserved RNA-binding protein, in CHOL progression, particularly its involvement in metastasis and immune microenvironment regulation. Using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we investigated MBNL3 expression and its correlation with patient prognosis. High MBNL3 expression was associated with significantly better overall survival (OS), progression-free survival (PFS), disease-specific survival (DSS), and disease-free interval (DFI) in CHOL patients. Functional analysis revealed that MBNL3 modulates epithelial-mesenchymal transition (EMT) and interacts with critical pathways, including focal adhesion, collagen signaling, and TNF signaling. Additionally, MBNL3 influences immune cell infiltration, with high expression linked to increased macrophage and Th17 cell presence, suggesting potential roles in immune response modulation. Experimental validation confirmed that silencing MBNL3 promotes EMT, enhances tumor cell migration and invasion, and increases metastasis in vivo. Furthermore, genetic analyses highlighted the impact of MBNL3 mutations and methylation on CHOL progression, identifying potential targets for immunotherapy. This is the first study to investigate MBNL3's role in CHOL, positioning it as a prognostic biomarker and a promising therapeutic target for improving outcomes in CHOL patients. Further research is needed to elucidate the molecular mechanisms underlying MBNL3's regulation of tumor metastasis and the immune microenvironment.

Talquetamab is a first-in-class GPRC5DxCD3 bispecific antibody approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM), and this multicenter retrospective analysis of 114 RRMM patients treated between October 2023 and January 2025 demonstrated significant efficacy in a heavily pretreated population with median 6 prior therapies. All patients were triple-class refractory, 79% were penta-refractory, and 65% had received prior BCMA-targeted therapy. The overall response rate was 73%, including complete response in 26% and very good partial response in 26%, with six-month progression-free and overall survival rates of 56 and 86% respectively and median progression-free survival of 10 months. Common adverse events included cytokine release syndrome (CRS; 54% with grade ≥2 in 7.3%), infections (27%), and immune effector cell-associated neurotoxicity syndrome (9.8%). The 3-month cumulative infection incidence of 14% for both bacterial and viral infections, where 59% were viral and 41% bacterial, grade ≥3 infections occurred in 18%, and intravenous immunoglobulin was used in 61% of patients. Significant weight loss was observed, with a mean 8.8% decrease at 6 months. This real-world analysis confirms talquetamab's efficacy in heavily pretreated RRMM while highlighting notable toxicities, including progressive weight loss and infections, which require rigorous monitoring and proactive supportive care.

Gastric cancer (GC) metastasis remains a major cause of poor prognosis, yet its molecular drivers are poorly understood. Here, we integrated single-cell RNA sequencing (scRNA-seq) of primary tumors and matched metastatic lymph nodes from six GC patients to identify a metastatic epithelial subpopulation characterized by EGR4 overexpression. Kaplan-Meier analysis revealed that high EGR4 expression correlated with reduced survival in GC patients. Mechanistically, chromatin immunoprecipitation sequencing (ChIP-seq) and luciferase assays demonstrated that EGR4 directly bound to the GDF15 promoter, driving its transcriptional activation. Functional studies showed that EGR4 promoted migration and metastasis via GDF15-mediated ErbB3/ErbB1 hetero-dimerization, which activated PI3K/AKT and MAPK/ERK pathways. Furthermore, CellChat analysis identified robust interactions between EGR4+ GC cells and cancer-associated fibroblasts (CAFs), particularly extracellular matrix (ECM)-remodeling eCAFs. Secreted GDF15 induced CAF activation through TGF-β receptor signaling, creating a pro-metastatic niche. Collectively, our study establishes the EGR4/GDF15 axis as a critical driver of GC metastasis, offering possible therapeutic targets for intervention.

Long non-coding RNAs (lncRNAs) and RNA N⁶-methyladenosine (m6A) have been linked to leukemia drug resistance. However, whether and how lncRNAs and m6A coordinately regulate resistance remain elusive. Here, we show that many differentially expressed lncRNAs enrich m6A, and more lncRNAs tend to have higher m6A content in CML cells resistant to tyrosine kinase inhibitors (TKIs). We demonstrate the broad clinical relevance of our findings, showing that upregulation of top-ranked lncRNAs (e.g., SENCR, PROX1-AS1, LINC00892) in TKI-resistant cell lines occurs in CML patients at the diagnostic stage, blast crisis phase, or not responding to TKIs compared to the chronic phase or TKI responders, respectively. Higher lncRNAs predict drug resistance and shorter survival duration. The knockdown of SENCR, PROX1-AS1, or LINC00892 restores TKI sensitivity. Mechanistically, upregulation of PROX1-AS1, SENCR, and LINC00892 results from FTO-dependent m6A hypomethylation that stabilizes lncRNA transcripts and empowers resistant cell growth through overexpression of PI3K signaling mediators (e.g., ITGA2, F2R, COL6A1). Treatment with PI3K inhibitor alpelisib eradicates resistant cells in vitro and in vivo, with prolonged survival of leukemic mice through downregulation of F2R, ITGA2, and COL6A1. Thus, the lncRNA-m6A-PI3K cascade represents a new non-genetic predictor for drug resistance and poorer prognosis in cancer, and a pan-cancer mechanism underlying TKI resistance.

SET domain-containing 7 (SETD7, also known as KMT7 or SET7/9), a histone lysine methyltransferase (HKMT) responsible for catalyzing histone H3 lysine 4 monomethylation (H3K4me1), has emerged as a key regulator in multiple cancers. However, the biological functions and epigenetic regulatory mechanisms of SETD7 in esophageal squamous cell carcinoma (ESCC) remain unclear. Our study found that SETD7 expression is significantly upregulated in ESCC tissues and positively correlates with clinical staging. Functional analyses revealed that SETD7 promotes ESCC cell proliferation and migration in vitro, while accelerating tumor growth in vivo. Additionally, SETD7 knockdown increased ESCC cell sensitivity to ferroptosis induction, indicating its dual functionality in tumorigenesis and ferroptosis resistance. Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing analysis systematically mapped H3K4me1 modifications in ESCC cells, identifying ALDH1A3 (aldehyde dehydrogenase 1 family member A3) as a key downstream target. Mechanistically, SETD7-mediated H3K4me1 deposition at the ALDH1A3 promoter drives transcriptional activation, increasing the level of reduced coenzyme Q10 (CoQ10H₂) and inhibiting lipid peroxidation. This study reveals a novel epigenetic-metabolic axis (SETD7-H3K4me1-ALDH1A3/NADH/CoQ10H₂) that regulates ESCC progression and ferroptosis sensitivity, which highlights the clinical translational value of SETD7 in ESCC prognosis assessment and therapeutic development. Schematic diagram illustrating the mechanism by which SETD7 accelerates ESCC progression through enhancing ferroptosis resistance. Created with BioRender.

To enhance the effectiveness of irradiation (IR) and optimize PD-1/PD-L1 blockade therapy for hepatocellular carcinoma (HCC), we conducted in vivo CRISPR-Cas9 metabolic sublibrary screening, pinpointing UDP-glucose dehydrogenase (UGDH) as a key target. Post-IR, protein kinase R (PKR) translocates to the nucleus. There, elevated UGDH produces UDP-GlcUA, which binds PKR's dsRNA-binding domain (dsRBD). This binding triggers PKR dimerization, autophosphorylation (T451), and activation. Activated PKR then phosphorylates TOP2A at S1467, inducing its liquid-liquid phase separation (LLPS) and enhancing topoisomerase activity, and finally protects tumor cells from IR-induced DNA damage. Disrupting the UDP-GlcUA/PKR complex reduces TOP2A-S1467 phosphorylation, lowers topoisomerase activity, increases cGAS-STING signaling, and improves anti-PD-L1 immunotherapy efficacy. Clinical HCC sample analysis confirmed the relevance of UDP-GlcUA and the phosphorylation of PKR and TOP2A in response to radiation. Critically, blood UDP-GlcUA may serve as a biomarker for PKR/TOP2A axis activation, guiding patient suitability for anti-PD-L1 immunotherapy after IR and enabling personalized treatment strategies.

Understanding therapy resistance requires deconvolving heterogeneous cell populations and tracking clonal trajectories. While CRISPR-based cellular barcoding is powerful for lineage tracing, many platforms suffer from low efficiency and limited compatibility with single-cell transcriptomics. We developed Oligo-CALL (Oligonucleotide-inducible CRISPR transcriptional activator-Assisted Lineage Labeling), an advanced barcoding system enabling precise lineage tracing, live clone isolation, and seamless integration with single-cell RNA sequencing. Applied to lung cancer cells treated with a KRASG12C inhibitor, Oligo-CALL identified clones consistently enriched posttreatment, supporting a model of predestined resistance. Oligo-CALL achieved >95% efficiency in linking lineage identity to transcriptomes, uncovering diverse clone-specific pathways with underlying resistance. Paired analysis of barcode-matched clones from naïve and resistant populations revealed transient and fixed resistance phenotypes. Notably, DNA repair pathways are recurrently altered in resistant clones, and inhibition of poly(adenosine 5'-diphosphate-ribose) polymerase synergizes with KRAS G12C inhibition to overcome resistance. Together, Oligo-CALL provides a versatile platform for dissecting lineage evolution and molecular dynamics of targeted therapy resistance.

Survival rates in the European population with gastric and gastroesophageal junction (G/GEJ) adenocarcinoma remain low. Epidemiologic research is warranted to understand the population size, unmet need, and current treatment patterns of G/GEJ adenocarcinoma. The objective of this research was to develop an algorithm to link patients across the FRench EsoGAstric Tumours (FREGAT) and Système National des Données de Santé (SNDS) databases to develop a real-world dataset for G/GEJ adenocarcinoma.

The LRIG gene family consists of LRIG1-3. While LRIG2 has been described as a tumor promoter, LRIG1 and LRIG3 have been identified as tumor suppressors in previous literature. Because of these contrasting roles, the expression of LRIG1-3 was examined across different grades of glioma, between primary and secondary glioblastoma and with focus on chemotherapy treatment. Human tumor tissue samples were extracted during neurosurgery and grouped among the WHO classification valid at the time of surgery. Quantitative western blot analysis, qPCR and immunofluorescence staining were performed. LRIG1 was less expressed in glioma compared to peritumoral tissue with additional decrease with ascending tumors grade. Further, secondary glioblastoma expressed more LRIG1 protein than primary. On mRNA level, the same was seen for LRIG2, were low grade glioma expressed significantly more LRIG2 than high grade glioma. And on protein level, secondary glioblastoma showed higher expression than primary. LRIG3 mRNA expression, in contrast, was significantly higher in grade II gliomas compared to surrounding control tissue, whereas chemotherapy did not significantly affect expression levels in glioblastoma. Our results reinforce suggestions that LRIG1-3 could function as diagnostic markers and therapeutic targets in the treatment of gliomas.

Colorectal Cancer (CRC) is the third most prevalent malignancy, leading to significant morbidity and mortality globally. Epidemiological studies suggest that chronological age and diet are among the major contributing factors correlated with the incidence of CRC. Our study aimed to provide insights into the association between age, diet, and gut microbiome in CRC using molecular techniques including RNA sequencing, cytokine analysis, and metagenomic analysis. We used syngeneic MC38 mice model divided into two age groups (old and young) and three diet groups (standard chow, calorie-restricted and high-fat). The major findings of this study are that age and diet impact intratumoral gene signaling (nuclear and mitochondrial), and hub genes we identified are associated with prognosis in CRC. Fecal microbiome analysis showed that old microbiomes have higher alpha diversity compared to young mice. Our results demonstrate that interactions between host (age) and external (diet) factors regulate tumor growth mediated by cytokines, mitochondrial derived proteins, and the gut microbiome. Collectively, our findings advance current understanding of the mechanisms by which aging, diet and gut microbiota impact CRC onset and progression though further investigation is warranted.

Nephrogenic adenoma (NA) is an extremely rare benign tumor in children that may be misdiagnosed as malignant.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, highlighting the critical need for the development of innovative and effective therapeutic strategies. Baicalein, a bioactive flavonoid derived from Scutellaria baicalensis, has emerged as a promising anticancer agent with multifaceted effects against colorectal cancer. This work summarizes into the molecular and immunomodulatory mechanisms underlying baicalein's anticancer activity. Baicalein inhibits proliferation, suppresses metastasis, induces apoptosis, and modulates key pathways like PI3K/Akt, MAPK, and TLR4/NF-κB. It enhances the tumor microenvironment by promoting immune cell infiltration, regulating cytokines, and activating CD4 + and CD8 + T cells, amplifying antitumor immunity. By targeting critical oncogenic and immune pathways, baicalein disrupts tumor progression while simultaneously enhancing immune recognition and suppressing tumor-promoting mechanisms in CRC. Additionally, baicalein influences redox homeostasis by modulating reactive oxygen species (ROS) generation and restoring oxidative balance, thereby impacting cancer cell survival and proliferation. Its anti-oxidative properties further mitigate tumor-promoting oxidative stress while sensitizing CRC cells to apoptosis. Baicalein have poor solubility and rapid metabolism limits its effectiveness against colorectal cancer, where nanotechnology-based drug delivery can overcome these challenges. By using nanoparticles (NP) and other nano-carriers to improve stability, targeting, and controlled release, baicalein's anticancer potency and safety can be significantly enhanced for future CRC therapies. Thus, baicalein-NP conjugates can strengthen the immune defense and blocks cancer-promoting signals in colorectal cancer.

Gastrointestinal (GI) malignancies represent a significant global health burden, characterized by high mortality rates and profound resistance to conventional therapies. This necessitates the exploration of novel therapeutic vulnerabilities, and two recently discovered forms of regulated cell death, ferroptosis and cuproptosis, offer promising metabolism-centered strategies. Ferroptosis is a non-apoptotic pathway driven by iron-dependent lipid peroxidation, canonically suppressed by the glutathione peroxidase 4 (GPX4) axis. In contrast, cuproptosis is a distinct process wherein excess copper induces lethal proteotoxic stress through direct binding to lipoylated components of the tricarboxylic acid (TCA) cycle. Critically, these pathways are not mutually exclusive; instead, they are intricately connected through shared molecular nodes and metabolic dependencies, including redox homeostasis, key signaling proteins, and mitochondrial integrity. This review systematically examines the molecular crosstalk between ferroptosis and cuproptosis, highlighting the synergistic potential of their co-activation as a powerful anti-cancer strategy in GI tumors. We systematically evaluate both preclinical evidence and clinical studies for therapeutic interventions, ranging from small-molecule inducers to advanced nanoplatforms and immunotherapy combinations. Furthermore, we discuss the pressing challenges of identifying predictive biomarkers for patient stratification and overcoming adaptive resistance. Ultimately, deciphering the ferroptosis-cuproptosis nexus holds immense potential to unlock a new paradigm of synergistic therapies, paving the way for more effective clinical management of GI malignancies.

IntroductionIn low-risk prostate cancer (PCa), the aim of active surveillance (AS) is to reduce overtreatment and avoid potential adverse effects. The rebiopsy approach in AS remains debated, spanning routine scheduled biopsies to clinically- or imaging-driven rebiopsies based on PSA kinetics or multiparametric MRI (mpMRI). In this retrospective, single-center comparative cohort study, we examined outcomes of periodic vs patient-based rebiopsy during AS and evaluated oncological outcomes in patients with PCa.MethodsSeventy-four patients who underwent at least one year of AS for PCa between January 2019 and July 2024 were retrospectively analyzed. Two distinct AS protocol patients were included in the study from 4 different physicians in our clinic. Demographic data, PSA levels, PSA kinetics, mpMRI findings, and rebiopsy pathology results were documented. Radical prostatectomy (RP) pathology results and factors influencing definitive treatment (DT) decisions were compared between the 2 groups: periodic rebiopsy (n = 41), and patient-based rebiopsy (n = 33).ResultsThe median rebiopsy time was shorter in the periodic group (12.5 months, IQR: 1) than in the patient-based group (14 months, IQR: 9; P < 0.001). First-year rebiopsies were more frequent in the periodic group (68.3%) than in the patient-based group (45.5%; P = 0.048). No significant difference in DT switching rates or final pathology outcomes was observed, though patients in the periodic group switched to DTs earlier (P = 0.045). A positive Spearman's correlation was identified between the maximum PSA density and the International Society of Urological Pathology (ISUP) score of RP specimens [rho = 0.62, P = 0.001]. A PSA density cut-off value of ≥0.17 ng/mL2 was found to predict an ISUP grade ≥2 in the final pathological assessment with high accuracy (AUC = 0.891, 95% CI: 0.753-1.00, P = 0.003).ConclusionsPatient-based rebiopsy protocols driven by PSA kinetics and mpMRI results can minimize unnecessary procedures, prevent overtreatment, and optimize monitoring in AS of PCa.

This paper illustrates a method to map cognitive subcortical white matter pathways in brain tumour surgery, in patients not eligible for awake intraoperative mapping. The latter being the gold standard, it is not feasible in all patients. Illustrated by three cases, the presented method includes a preoperative mapping of both motor and subcortical eloquent structures - such as arcuate fasciculus and basal ganglia - subsequentially using subcortical motor mapping as a landmark to indirectly identify the cognitive structures.

Oral squamous cell carcinoma (OSCC) is the most common oral malignancy, often associated with poor outcomes due to metastasis and late detection. The epithelial-to-mesenchymal transition (EMT) is central to OSCC progression, but the prognostic role of EMT markers remains unclear. This systematic review and meta-analysis evaluated five key EMT markers-E-cadherin, EpCAM, Vimentin, TWIST, and SNAIL-in OSCC.

Pleomorphic adenoma (PA) is the most common benign salivary gland tumor, yet its histologic diversity can resemble malignant neoplasms, posing diagnostic challenges. Molecular characterization, including fusion gene analysis, can aid in distinguishing these cases.

Amino acids are fundamental biomolecules that constitute the building blocks of proteins. Monitoring their dysregulation and fluctuations serves as an important indicator of human health. The aim of this study is to explore the role of exogenous amino acids metabolism in colon cancer development. Raman spectroscopy and Raman imaging were employed to investigate biochemical changes in normal human colon cells (CCD-18Co) and cancerous colon cells (Caco-2), both untreated and supplemented with leucine, threonine, and arginine. Spectroscopic data were analyzed using chemometric methods, specifically Partial Least Squares Discriminant Analysis (PLS-DA). Raman spectroscopy, combined with chemometric approach, identified unique Raman biomarkers - 1088/1262, 1444/1660, 1580/1004, and 1630/1444 - that correspond to changes in nucleic acids, lipids/lipids+Amide I, proteins, and lipids, respectively, in both normal and cancer cells supplemented with amino acids. These findings underscore the significant potential of Raman spectroscopy and Raman imaging as powerful tools for investigating the role of exogenous amino acids in colon cancer progression. We have also shown that the S₁-state lifetime of tetra-sulphonated aluminum phthalocyanine remains unaffected by amino acid supplementation, as confirmed by femtosecond transient absorption spectroscopy, supporting its stability as a photosensitizer for photodynamic therapy.

Gains of chromosome 12p11.21, encoding for the cancer-specific lncRNA LISRR, correlate with poor survival across different cancers. In melanoma, LISRR is upregulated in immunotherapy-resistant patients to contribute to the generation of drug-tolerant cells by activating an immune-suppressive translational program, affecting the synthesis of PD-L1 and of the glycocalyx. Accordingly, downregulation of LISRR initiates robust immune responses and resensitizes to immunotherapy ex vivo and in vivo. The use of glycans to evade immunity exhibits shared characteristics with the testis, where defects in the glycocalyx cause infertility. Mechanistically, we showed that LISRR affects the ribosome core composition and recruits deleted in azoospermia-associated protein 1 to polysomes to prime the integrated stress response. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based strategy to overcome resistance to immune checkpoint blockade.

Decreased tobacco use has resulted in substantial declines in the prevalence of upper aerodigestive tract malignancies. However, the prevalence of oral cavity squamous cell carcinomas has been steadily increasing despite decreases in tobacco-related malignancies both within the United States and worldwide. The cause driving the increasing prevalence is unknown and may reflect a combination of viral, environmental, and genetic mechanisms. Radiologists must be familiar with the imaging appearance of oral cavity carcinomas to achieve proper staging and to guide surgical and/or radiation therapy management. This article will review the emerging trends in oral cavity carcinoma, the basics of oral cavity anatomy relevant to subsites of cancer involvement, the imaging appearance of this entity, and the information critical for appropriate staging to direct surgical management, medical treatment, and/or radiation therapy. Keywords: Ear/Nose/Throat, Head/Neck, Tongue, Neoplasms-Primary, Oncology, CT, MR Imaging, Diagnosis, PET/CT, PET/MRI © RSNA, 2025.